JPH10504544A - Novel uses of derivatives of imidazole, novel derivatives of imidazole, methods for their production, novel intermediates obtained, their use as drugs and pharmaceutical compositions containing them - Google Patents

Abstract

(57) [Summary] The present invention provides the following formula (I): Wherein R ₁ is hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, formyl, cycloalkyl, (which may be interrupted by a heteroatom), R ₂ and R ₃ are especially halogen, mercapto, acyl, carboxy, nitro, cyano, amino, carbamoyl, R _4, -OR ₄ (wherein, R ₄ is particularly hydrogen, alkyl, alkenyl, alkynyl, acyl, _{amino, - (CH 2) m1 -S} (O) m2 -X -R ₁₀ (m1 is 0 to 4, m @ 2 is 0 to 2, X is a single bond or a -NH -, - NH-CO - , - NH-CO-NH- and represents, R ₁₀ is alkyl, alkenyl or Y represents an aryl which may be substituted. Which are in all isomeric and salt forms thereof and their use as medicaments.

Description

DETAILED DESCRIPTION OF THE INVENTION     Novel uses of derivatives of imidazole, new derivatives of imidazole,     Methods for their production, novel intermediates obtained, their use as drugs     And pharmaceutical compositions containing them   The present invention relates to a novel use of a derivative of imidazole, a novel derivative of imidazole , Their preparation, novel intermediates obtained, their use as pharmaceuticals and it And pharmaceutical compositions containing them.   Thus, the subject of the present invention is the following formula (I) [here,   R₁Is hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alk A quinthio group (each of these groups is linear or branched; at most 12 Contains carbon atoms. ), Formyl group or cycloalkyl group (one or more hetero It may be interrupted by atoms and contains 3-7 carbon atoms. ) , All of these groups are halogen atoms, the following groups: hydroxyl, free, salt-forming Carboxyl groups, esterified or amidated, cyano, nitro Amino (one or two identical or containing at most 6 carbon atoms) It may be substituted by different alkyl groups. ) Containing from 3 to 7 carbon atoms Cycloalkyl, alkyl containing at most 6 carbon atoms, alkenyl And alkoxy groups, haloalkyl, alkylthio, haloalkylthio, haloa Lucoxy, phenoxy, phenylalkoxy, optionally substituted carbamoy , Acyl, acyloxy, tetrazolyl and phenyl which may be salted (Halogen, hydroxyl, alkyl containing at most 4 carbon atoms) And alkoxy groups, trifluoromethyl, cyano, free, salted and Is one or more selected from esterified carboxy and tetrazolyl groups May be substituted by a group. One or more same or different selected from May be substituted by a group,   R_TwoAnd R_ThreeMay be the same or different,   (A) halogen atoms, the following groups: mercapto, acyl, free, salted, Esterified or amidated carboxy or carboxycarbo Nil, nitro, cyano and -P (O) (OR)_TwoGroup (where R is a hydrogen atom, Represents an alkyl or phenyl group. ), And   (B) R_FourAnd -OR_FourBase {here, ・ R_FourIs       − (CH_Two)_m1-S (O)_m2-X-R_Ten (Where m1 represents an integer of 0 to 4, m2 represents an integer of 0 to 2,   X-R_TenRepresents an amino group, or   X is a single bond or -NR₁₁-, -NR₁₁-CO-, -NR₁₁-CO-O-, -N R₁₁-CO-NR₁₂-And -N = CR₁₁-NR₁₂-Represents a group and R_TenIs archi Represents an alkyl, alkenyl or aryl group, these groups being a halogen atom, the following groups: Hydroxyl, cycloalkyl containing from 7 to 7 carbon atoms, at most 6 Linear or branched alkyl, alkoxy, haloalkyl containing carbon atoms , Alkylthio, haloalkylthio and haloalkoxy groups, phenoxy, phenyl Alkoxy, optionally substituted carbamoyl, acyl, acyloxy, Isolated, salted or esterified carboxy groups, tetrazolyl, Ano, nitro, amino (one or two containing at most 6 carbon atoms) They may be substituted by the same or different alkyl groups. ) And aryl (Halogen, hydroxyl, alkyl containing at most 4 carbon atoms) And alkoxy groups, trifluoromethyl, free, salted or ester By one or more groups selected from carboxy groups and tetrazolyl groups It may be substituted. By one or more identical or different groups selected from May be substituted,   R₁₁And R_TenMay be the same or different, a hydrogen atom and R_TenAbout Selected from the defined meanings. ) Represents a group of ・ R_FourIs a hydrogen atom; alkyl, alkenyl, alkynyl and acyl groups (these are The radical is linear or branched, contains at most 6 carbon atoms, and contains sulfur, oxygen Or may be interrupted by one or more heteroatoms selected from a nitrogen atom . An amino or carbamoyl group (one containing at most 6 carbon atoms) Or two identical or different alkyl or alkenyl groups or Like-(CH_Two)_m1-S (O)_m2-X-R_TenMay be substituted by a group. ); Represents a cycloalkyl group or an aryl group containing 3 to 6 carbon atoms, R_FourAlkyl, alkenyl and aryl groups in all of the groups which may be represented by Is A halogen atom, -Hydroxyl, mercapto, cyano, azide, nitro, -SO_ThreeH, free, A salted, esterified or amidated carboxy group, -The following groups: alkyl, alkenyl, alkoxy, haloalkyl, alkylthio, Alkenylthio, alkynylthio, acyl, acyloxy, acylthio, haloa Alkylthio, haloalkoxy groups (these groups contain at most 6 carbon atoms) You. ), Aryl, arylalkyl, arylalkenyl, arylthio, a Reeloxy and arylalkoxy groups (where the aryl group is a halogen atom, Hydroxyl groups, alkyl and alkoxy containing at most 6 carbon atoms, Haloalkyl, alkylthio, haloalkylthio, haloalkoxy, substituted Carbamoyl, acyl, acyloxy, free, salted or Are esterified carboxy, cyano, nitro, amino (at most 6 carbon Substituted by one or two identical or different alkyl groups containing atoms It may be. ), Tetrazolyl and phenyl (halogen atom, the following groups: Droxyl, alkyl and alkoxy containing at most 4 carbon atoms, tri Fluoromethyl, free, salted or esterified carboxy and And may be substituted with one or more groups selected from tetrazolyl and tetrazolyl. ) Or May be substituted by one or more same or different groups selected from ), as well as −Next equation (here,   R₆And R₇Or R₈And R₉May be the same or different, A hydrogen atom, -Amino acids, Alkyl and alkenyl groups containing at most 6 carbon atoms (halogen atoms Selected from a hydroxyl group or an alkoxy group containing at most 6 carbon atoms May be substituted by one or more identical or different groups. ), Aryl, arylalkyl and arylalkenyl groups, wherein the linear or Represents a branched alkyl and alkenyl group containing at most 6 carbon atoms, and These aryl, arylalkyl and arylalkenyl groups are halogen atoms , Hydroxyl, nitro, cyano, alkyl containing at most 6 carbon atoms Alkenyl, haloalkyl, alkoxy and acyl groups, amino groups (at most 6 To one or two identical or different alkyl groups containing two carbon atoms It may be more substituted. ), Free, salted or esterified Carboxyl, aryl and arylalkyl groups (the latter two groups being halogen Atom, hydroxyl, trifluoromethyl, nitro, cyano, free, salt-formed Selected from carboxyl and tetrazolyl groups, which have been substituted or esterified It may be substituted by more than one group. By one or more groups selected from It may be substituted. ),as well as -As described above-(CH_Two)_m1-S (O)_m2-X-R_TenBase Selected from, or   R₆And R₇Or R₈And R₉Together with the nitrogen atom to which they are attached A 5-, 6- or 7-membered monocyclic group or a group consisting of an 8- to 14-membered condensed ring (this The same or different groups may be one or more selected from oxygen, nitrogen and sulfur atoms. It may contain other heteroatoms, and may contain halogen atoms, hydroxyl, Toro, cyano, alkyl, alkenyl, ha containing up to 6 carbon atoms Alkyl, alkoxy and acyl groups, amino groups (containing at most 6 carbon atoms) Substituted by one or two identical or different alkyl groups You may. ), Free, salted, esterified or amidated Carboxyl, aryl and arylalkyl groups (the latter two groups being halogen Atom, hydroxyl, trifluoromethyl, nitro, cyano, free, salt-formed Selected from substituted or esterified carboxy and tetrazolyl groups It may be substituted by one or more groups. By one or more groups selected from May be substituted. ) Or   R₈And R₉May be the same or different and represent an acyl group, or Is R₈Or R₉One is carbamoyl, alkoxycarbonyl or benzylo A carbonyl group and the other is R₈And R₉From the meaning defined above for Selected or R₈And R₉Together with the nitrogen atom to which they are attached To form a phthalimide or succinimide group. ) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y is the following equation     -Y₁-BY_Two ｛Here, Y₁Is an aryl group (a dioxol group and R_TwoAnd R_ThreeRepresented by It may be substituted by one or more groups selected from the groups obtained. )   B is Y₁And Y_TwoOr the following divalent group: —CO—, —O—, —NH— CO-, -CO-NH- or -O- (CH_Two)_p-(P is a value of 1, 2 or 3 Express. )   Y_TwoIs: ・ The meaning of B and Y_TwoIs Y₁Whether or not the same as_TwoIs Y₁To Is selected from the meanings described above, or -When B represents a single bond, Y_TwoIs a hydrogen atom, a halogen atom, a cyano group, An isolated, salted, esterified or amidated carboxy group; A tetrazolyl group or-(CH_Two)_m1-S (O)_m2-X-R_TenTable Forget Is defined as ｝ Represents a group of ] [This compound of formula (I) has all possible racemic, enantiomeric and And diastereomeric isomers. And inorganic compounds of the formula (I) Of the endothelin receptor in addition salts with organic and organic acids or with inorganic and organic bases For the manufacture of pharmaceutical compositions intended for the treatment of diseases arising from severe irritation. You.   A special subject of the invention is the induction of the compounds of formula (I) by endothelin Treatment of hypertension, treatment of all vasospasm and treatment of post-cerebral hemorrhage and renal failure, Manufactures a pharmaceutical composition intended to treat myocardial infarction and prevent recurrence of stenosis after angioplasty It is in use to do.   In the compounds of formula (I) as well as in the following description, The term "linear or branched alkyl group" preferably denotes the following groups: methyl, ethyl Propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl One of the tyl groups is represented by a pentyl or hexyl group, especially isopentyl and isohexyl. Xyl groups can also be represented. The term "linear or branched alkenyl group" preferably denotes the following groups: vinyl, Ryl, 1-propenyl, butenyl and especially one of the 1-butenyl or pentenyl groups Is shown. The term "linear or branched alkynyl group" is preferably ethynyl, propalyl; Represents a gil, butynyl or pentynyl group.   Alkyl groups interrupted by one or more heteroatoms include, for example, methoxy Cimethyl, methoxyethoxymethyl, propylthiopropyl, propyloxyp Ripyl, propylthioethyl and methylthiomethyl can be mentioned. The term “halogen” preferably denotes a chlorine atom, but is fluorine, bromine or iodine Elementary atoms can also be represented. The term "linear or branched alkoxy group" is preferably methoxy, ethoxy , Propoxy or isopropoxy, but n-, sec- or t-butoxy Groups can also be represented. The term "acyl group" preferably denotes an acyl group having 1 to 6 carbon atoms, For example, it represents a formyl, acetyl, propionyl, butyryl or benzoyl group, , Pentanoyl, hexanoyl, acryloyl, crotonoyl or carbamoyl And derivatives of carbonyl groups, such as, in particular, cycloalkylcarbonyl groups. I can do it. -The term "acyloxy group" means, for example, that the acyl group has the abovementioned meaning Group, preferably formyloxy, acetyloxy, propynyloxy, Shows a butyryloxy or benzoyloxy group. The term "cycloalkyl group optionally interrupted by one or more heteroatoms" Are preferably cyclopropyl, cyclobutyl groups, especially cyclopentyl and A clohexyl group or one or more atoms selected from oxygen, nitrogen or sulfur atoms Represents a carbocyclic group interrupted by, especially a dioxolane or dioxane group. The term "haloalkyl" preferably denotes, for example, bromoethyl, trifluoro As in the methyl, trifluoroethyl or pentafluoroethyl groups. The alkyl group is as described above and is at least one of the halogen atoms described above. Represents a substituted group. The term “haloalkoxy group” preferably denotes, for example, bromoethoxy, trif In the methoxy, trifluoroethoxy or pentafluoroethoxy groups As described above, the alkoxy group is as defined above and the halogen atom described above. A group substituted by one or more groups is shown. The term "aryl group" means a 5, 6 or 7 membered unsaturated monocyclic group or 8-14 And a carbocyclic or heterocyclic group consisting of a fused ring. Heterocyclic groups are oxygen, nitrogen Or one or more heteroatoms selected from sulfur atoms. When these heterocyclic groups contain more than one heteroatom, these heterocyclic groups It is to be understood that the heteroatoms of the groups can be the same or different.   Examples of such aryl groups include the following groups: phenyl, naphthyl, 2-thier Thienyl such as nil and 3-thienyl; furyl such as 2-furyl; Pyridyl, pyrimidinyl, pyrrolyl, thiazolyl such as jyl and 3-pyridyl , Isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, salted Tolazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, Oxadiazolyl, 3- or 4-isooxozolyl groups, and sulfur, nitrogen and acids Fused heterocyclic groups containing at least one heteroatom selected from elementary atoms, eg For example, benzothienyl such as 3-benzothienyl, benzofuryl, benzofurani Benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl , Indolyl, indolinyl, quinolyl or isoquinolyl, purinyl groups be able to. The term “arylalkyl group” means an alkyl and an aryl group Represents a group that can take the meaning as described above for the group. Ants like this Examples of benzylalkyl groups include the following groups: benzyl, diphenylmethyl, triphenyl Such as nilmethyl, naphthylmethyl, indenylmethyl, 2-thienylmethyl Thienylmethyl, furylmethyl such as furfuryl, pyridylmethyl, pyridyl Ethyl, pyrimidinylmethyl or pyrrolylmethyl groups are mentioned. These limitations In the listing of examples of non-specific groups, for example, phenylethyl, phenylpropyl and As in phenylalkyl, such as phenylbutyl, It should be understood that it can be represented as such by an ethyl, propyl or butyl group . The term "arylalkenyl and arylalkynyl" means the alkenyl Or an alkynyl group and an aryl group are each as defined above for these groups Shows a group that can have meaning. Examples of such arylalkenyl groups include For example, the above example of an arylalkyl group, wherein the alkyl group is alkenyl Such as replaced by a phenylvinyl or phenylallyl group is there. In these groups, the phenyl group may further be a naphthyl, pyridyl group or It is understood that it can be replaced by one of the aryl groups as defined. I want to. Examples of the arylalkynyl group include, for example, a phenylethynyl group. No.   Examples of an alkyl group substituted by an aryl group include, for example, those defined above. Such arylalkyl groups.   Examples of alkenyl groups substituted by an aryl group include, for example, those defined above. Such arylalkenyl groups can be mentioned. The term “aryloxy group” preferably denotes, for example, Thus, the aryl group is the same as described above. The term "arylalkoxy" preferably denotes, for example, benzyloxy, An aryl group and a phenylethoxy or phenylisopropoxy group, Indicate groups wherein the alkoxy group represents a group as defined above. The term “arylthio” preferably means, for example, phenylthio, pyridylthio O, pyrimidinylthio, imidazolylthio or N-methylimidazolylthio groups As described above, an aryl group represents a group as described above. The term "alkylthio" preferably denotes, for example, methylthio, ethylthio, Propylthio, isopropylthio, butylthio, sec-butylthio, t-butyl An alkyl group, as in a ruthio, isopentylthio or isohexylthio group Represents a group as defined above. For example, hydroxymethylthio or May be substituted like an aminoethylthio group. The term "haloalkylthio" preferably denotes, for example, bromoethylthio, Trifluoromethylthio, trifluoroethylthio or pentafluoroethylthio The alkyl group is as described above and the halogeno is as defined above. A group which is substituted by one or more of the substituent atoms. The term `` arylalkylthio, i.e. alkylthio substituted by aryl “O group” indicates, for example, a benzylthio or phenethylthio group.   R as described above₁, R_Two, R_ThreeAnd R_FourAll of the groups represented or held by Wherein the sulfur atom is, on the one hand, an alkylthio, an arylthio and a cycloalkyl Not oxidized as in a thio group, for example a cyclohexylthio group. Or, on the other hand, alkylsulfinyl, cycloalkylsulfinyl, Arylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl or It may be oxidized to give a reelsulfonyl group. The term “alkylsulfinyl and alkylsulfonyl groups” means their linear or Groups wherein the branched alkyl group has, for example, the meaning given above for an alkyl group And a thio group oxidized to a sulfinyl or sulfonyl group Represents an o group. For example, methylsulfinyl, ethylsulfinyl, methylsulfo Nyl and ethylsulfonyl groups. The term "arylsulfinyl and arylsulfonyl" means the aryl Represents a group wherein the group has the meaning given above for an aryl group, for example, and An arylthio group in which the group has been oxidized to a sulfinyl or sulfonyl group. An example For example, phenylsulfinyl or sulfonyl, pyridylsulfinyl or Is sulfonyl, pyrimidylsulfinyl or sulfonyl, imidazolyl sulf Finyl or sulfonyl, or N-methylimidazolylsulfinyl or Is a sulfonyl group.   Represented by one or more optional substituents of the groups defined in the compounds of formula (I) Carbamoyl and amino groups which can be carried or retained are A group in which two identical or different groups are bonded, A linking group such as is derived from a hydrogen atom to provide an amino group and -Or an alkyl group as described above to give a dialkylamino group (linear or Is a branched alkyl group containing from 1 to 6 carbon atoms. ). Ma Also, all of these groups may be substituted as described above and as described below.   R₆, R₇, R₈And R₉A carbocyclic or heterocyclic group that can be represented by The meanings defined above for these groups, in particular: phenyl, benzyl, phenyl Phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl , Pyridyl, pyrrolidinyl, piperidino, morpholino, piperazinyl groups Can be These groups include, for example, methylpiperazinyl, fluoromethylpi Perazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazin Substituted by one or more groups as described above, such as benzyl or benzylpiperazinyl. It may be.   On the other hand, R₆And R₇, On the other hand, R₈And R₉, And R₁₄And R_FifteenAs described above When, together with the nitrogen atom to which they are attached, form a heterocycle, This is, for example, the following rings: pyrrolyl, imidazolyl, indolyl, indolinyl, Purinyl, pyrrolidinyl, piperidino, morpholino, piperazinyl, imidazoly It is one of dinyl, pyrazolidinyl, thiomorpholinyl and azepine. these The groups may be represented by one or more groups as described above, especially chlorine and fluorine atoms, the following groups: Chill, ethyl, isopropyl, t-butyl, methoxy, ethoxy, propoxy, One selected from benzoyl, methoxycarbonyl, ethoxycarbonyl, etc. It may be substituted by the above groups. For example, methylpiperazinyl, fluoro Methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl Such as perazinyl or benzylpiperazinyl. The latter two bases Where phenyl and benzyl are aryl, arylalkyl and aryl As described above for the alkenyl group, for example, chlorophenyl or trifluoro May be substituted as in phenyl.   On the other hand, R₆And R₇, On the other hand, R₈And R₉Are the nitrogen sources to which they are attached Heterocycles which can be formed together with the offspring preferably represent saturated heterocycles.   Similarly, in the compounds of formula (I), the carbamoyl or amino group is Groups carried by the same or different groups and represent aliphatic or cyclic chains. Or together with the nitrogen atom to which they are attached, R₆, R₇ , R₈And R₉Can form a heterocyclic ring as described above.   An amino group which may be substituted and a carbamoyl group which may be substituted, In each case, one or two hydrogen atoms bonded to the nitrogen are selected from such groups. Means a group that can be substituted by one or two groups.   Accordingly, an optionally substituted amino group is, for example, a monoalkylamino group. For methylamino, ethylamino or isopropylamino, For dialkylamino groups, use dimethylamino, diethylamino or methyl. One selected from alkyl groups as described above, as in ruethylamino Or an amino group which may be substituted by two alkyl groups. these Alkyl groups include, for example, methoxymethyl, methoxyethyl and ethoxyethyl groups. As described above, it may be substituted as described above.   The term “optionally substituted carbamoyl group” is not limiting and is illustrative. Only one or two alkyl groups which may be substituted as described above. Especially when N-methylcarbamoyl, N-ethylcarbamoyl, etc. Monoalkylcarbamoyl group, or N, N-dimethylcarbamoyl, N, N-di N, N-dialkylcarbamoyl groups such as ethylcarbamoyl, N- (hydro N such as (xymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl -(Hydroxyalkyl) carbamoyl group, furthermore phenylcarbamoyl, Lysylcarbamoyl, benzylcarbamoyl, N-methyl-N-phenylcarba Substitution on nitrogen atom to form moyl, pyridylmethylcarbamoyl group, etc. Represents a carbamoyl group which may be substituted. Further, among the substituted alkyl groups, Carbamoylalkyl groups such as carbamoylmethyl or carbamoylethyl groups An alkyl group substituted by a carbamoyl group as described above to form Can be mentioned.   The amino group may be an alkoxycarbonylamino group, which is preferably Is a t-butyloxycarbonylamino group or a benzyloxycarbonylamino group It is.   Also, amino and carbamoyl groups are, in particular, 20 natural amino acids, Especially proline or for example glycine, alanine, leucine, isoleucine, valine Or selected from phenylalanine or other natural amino acids known to those skilled in the art. May be substituted by one or two amino acids as described.   Depending on whether m1 represents 0, 1, 2, 3 or 4,-(CH_Two)_m1-Group Represents a single bond, methylene, ethylene, propylene, isopropylene or butylene group Express.   The carboxyl groups of the compounds of formula (I) can be salt-formed from various groups known to those skilled in the art. Or it can be esterified. Among them, for example, I can do it. Among the compounds for salt formation, for example, the equivalent sodium, potassium, lithium Inorganic bases such as calcium, magnesium, or ammonium, or examples For example, methylamine, propylamine, trimethylamine, diethylamine, triamine Ethyl eramine, N, N-dimethylethanolamine, tris (hydroxymeth Tyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexyl Luamine, morpholine, benzylamine, procaine, lysine, arginine, Organic bases such as stidine, N-methylglucamine. -Among the compounds for esterification, for example, methoxycarbonyl, ethoxy Alcohols such as bonyl, t-butoxycarbonyl or benzyloxycarbonyl An alkyl group for forming a xycarbonyl group. These alkyl groups are, for example, , Chloromethyl, hydroxypropyl, methoxymethyl, propionyloxime To tyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups For example, halogen, hydroxyl, alkoxy, acyl, acyl Substituted by a group selected from the group consisting of Can be   Addition salts of compounds of formula (I) with inorganic or organic acids are, for example, the following acids: hydrochloric acid, odor Hydrofluoric acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, formic acid, benzoic acid Acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxy Silicic acid, aspartic acid, ascorbic acid such as methanesulfonic acid, ethanes Alkylmonosulfonic acids such as sulfonic acid, propanesulfonic acid, for example methane Alkyl disulfonic acids such as disulfonic acid, α, β-ethane disulfonic acid, Aryl monosulfonic acid such as benzene sulfonic acid, aryl disulfonic acid, etc. May be salts formed by   In a preferred compound of the invention, R_TwoAnd R_ThreeWhen both represent a sulfur group, R_TwoAnd R_ThreeMay be the same or different, and these sulfur groups are not necessarily the same. It has no oxidation number.   The subject of the present invention is the following formula (I)_A) [here,   R_1AIs hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, a Alkylthio groups (each of these groups is linear or branched; at most 12 Containing carbon atoms. ), Formyl group, cyclo containing 3-7 carbon atoms Represents an alkyl group or a dioxolan or dioxane group; Is a halogen atom, a hydroxyl, an alkoxy containing at most 6 carbon atoms And alkylthio groups, acyl, free, salted, esterified and Are amidated carboxy, cyano, nitro, and amino groups (at most six One or two identical or different alkyl groups containing It may be replaced. A) a cycloalkyl group containing from 3 to 7 carbon atoms; Phenyl group (halogen, hydroxyl, containing at most 4 carbon atoms Alkyl and alkoxy groups, trifluoromethyl, free, salted Or selected from esterified carboxy, cyano and tetrazolyl groups It may be substituted by one or more groups. One or more identical or May be substituted by different groups,   R_2AAnd R_3AMay be the same or different,   (A) halogen, mercapto, acyl, free, salted or Sterilized carboxy or carboxycarbonyl, nitro, cyano group, And   (B) R_4AAnd -OR_4ABase {here, ・ R_4AIs       − (CH_Two)_m3-S (O)_m2-X_A-R_10A (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_A-R_10ARepresents an amino group, or   X_AIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11A-Represents a group and R_10AIs alkyl, alke Represents a phenyl or aryl group, which may be a halogen atom, a hydroxyl group, Alkyl and alkoxy groups containing at least 4 carbon atoms, trifluoromethyl Group, nitro group, cyclohexyl group, cyclopentyl group, aryl group (halogen Atoms, hydroxyl groups, alkyls and alcohols containing at most 6 carbon atoms Xy, trifluoromethyl, free, salted or esterified Carboxy, cyano, nitro, amino groups (containing at most 4 carbon atoms May be substituted by one or two same or different alkyl groups. No. ) May be substituted with one or more groups selected from Selected from) May be substituted with one or more substituents   R_11AIs a hydrogen atom or R_10ARepresents the meaning defined for ) Represents a group of ・ R_4AAre hydrogen, alkyl, alkenyl and acyl groups (these groups are linear or Are branched, contain at most 6 carbon atoms, and contain sulfur, oxygen or It may be interrupted by one or more heteroatoms selected from nitrogen atoms. ) An amino group (one or two identical or containing at most 6 carbon atoms) May be substituted by a different alkyl group. ) 3 to 6 carbon atoms Represents a cycloalkyl group or an aryl group,_4AGroup represented by In all of the alkyl, alkenyl and aryl groups are --- halogen atom, --- hydroxyl, mercapto, cyano, azide, nitro, SO_ThreeH, free, Salt-formed, esterified or amidated carboxy groups, --- alkyl, alkenyl, alkoxy, haloalkyl, alkylthio, acyl , Acyloxy, acylthio, haloalkylthio, haloalkoxy groups (these The groups contain at most 6 carbon atoms. ), Aryl, arylalkyl, a Lylalkenyl, arylthio, aryloxy and arylalkoxy groups (Where the aryl group is a halogen atom, hydroxyl, at most 6 carbon atoms Alkyl and alkoxy groups containing trifluoromethyl, free, salt-formed Carboxyl, cyano, nitro, and amino groups One or two identical or different alkyls each containing 4 carbon atoms May be substituted by a phenyl group. ), Tetrazolyl and phenyl groups (halogen Alkyl and alkyl containing at most 4 carbon atoms, Coxy groups, trifluoromethyl and free, salted or esterified And may be substituted by one or more groups selected from the group consisting of a substituted carboxy group. ) And may be substituted by one or more same or different groups selected from ) ,as well as −−Next formula (here,   R_6AAnd R_7AOr R_8AAnd R_9AMay be the same or different, A hydrogen atom, Alkyl groups containing at most 4 carbon atoms (halogen atoms, hydroxyl One or more selected from groups or alkoxy groups containing at most 4 carbon atoms May be substituted by the same or different groups. ), Aryl and arylalkyl groups, wherein the linear or branched alkyl groups Contains at most 4 carbon atoms and has the aryl and arylalkyl Is a halogen atom, hydroxyl, nitro, cyano, trifluoromethyl, Alkyl, alkoxy and acyl groups containing at most 6 carbon atoms, amino Groups (one or two identical or different containing at most 4 carbon atoms) May be substituted by an alkyl group. ), Free, salted or Esterified carboxy, tetrazolyl and phenyl groups (halogen atom, Droxyl, trifluoromethyl, nitro, cyano, free, salted, young Or one or more selected from esterified carboxy and tetrazolyl groups May be substituted by a group of Substituted with one or more groups selected from It may be. ) Selected from, or   R_6AAnd R_7AOr R_8AAnd R_9AIs one of the nitrogen atoms to which they are attached A group consisting of a 5-, 6- or 7-membered monocyclic group or an 8- to 14-membered fused ring ( These same or different groups may be one or more selected from oxygen, nitrogen and sulfur atoms. May contain other heteroatoms, halogen atoms, hydroxyl, Nitro, cyano and trifluoromethyl groups, containing at most 6 carbon atoms Alkyl, alkoxy and acyl groups, amino groups (containing at most 4 carbon atoms Even if substituted by one or two identical or different alkyl groups Good. ), Free, salted, esterified or amidated Ruboxy, tetrazolyl, oxazolyl and phenyl groups (halogen atom, hydro Xyl, trifluoromethyl, nitro, cyano, free, salted or One or more groups selected from esterified carboxy and tetrazolyl groups May be substituted. Substituted by one or more groups selected from May be. ) Or   R_8AAnd R_9AMay be the same or different and represent an acyl group, or Iha R_8AOr R_9AOne of which is carbamoyl, alkoxycarbonyl or benzyl Represents a hydroxy group and the other is R_8AAnd R_9AThe meaning defined above for Selected from taste or R_8AAnd R_9AIs the same as the nitrogen atom to which they are attached. It forms a phthalimide or succinimide group. ) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y_AIs     -Y_1A-BY_2A ｛Here, Y_1AIs an aryl group (this is a dioxol group and R_2AAnd R_3ABy One or more groups selected from groups that may be represented may be more substituted. ) Represent,   B is Y_1AAnd Y_2AOr the following divalent group: —CO—, —O—, —NH— CO-, -CO-NH- or -O- (CH_Two)_p-(P is a value of 1, 2 or 3 Express. )   Y_2AIs: ・ The meaning of B and Y_2AIs Y_1AWhether or not the same as_2AIs Y_1A Is selected from the meaning described above, or -When B represents a single bond, Y_2AIs a hydrogen atom, a halogen atom, a cyano group, An isolated, salted, esterified or amidated carboxy group; A tetrazolyl group or-(CH_Two)_m3-S (O)_m2-X_A-R_10ABase Show Is defined as ｝ Represents a group of ] Of the formula [I_A) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_AInorganic) And corresponding to the addition salts with organic acids or with inorganic and organic bases of the above formula (I) The compound is in the application as described above.   A particular subject of the present invention is that of the formula (I_B) [here,   R_1BIs a linear or branched alkyl containing at most 6 carbon atoms, Represents a oxy or alkylthio group, or a dioxolan or dioxane group All of these groups are halogen atoms, hydroxyl groups and at most six carbon atoms. Containing alkoxy and alkylthio groups, acyl, free, salted, Esterified or amidated carboxy, cyano, nitro, amino Groups (one or two identical or different containing at most 6 carbon atoms) May be substituted by such an alkyl group. ) Containing 3-7 carbon atoms Cycloalkyl and phenyl groups (halogen, hydroxyl, at most Alkyl and alkoxy groups containing 4 carbon atoms, trifluoromethyl, Isolated, salted or esterified carboxy groups, cyano and tetra It may be substituted by one or more groups selected from a zolyl group. Select from) May be substituted with one or more same or different groups,   R_2BAnd R_3BMay be the same or different,   (A) halogen atoms, mercapto groups, free, salted or ester Carboxy or carboxycarbonyl groups, hydroxyl groups, many Also include alkoxy and acyl groups containing 6 carbon atoms, cyano groups, nitro groups, Nzoyl group, and   (B) R_4BAnd -OR_4BBase {here, ・ R_4BIs       − (CH_Two)_m3-S (O)_m2-X_B-R_10B (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_B-R_10BRepresents an amino group, or   X_BIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11B-Represents a group,_10BIs methyl, ethyl, Ropyl, vinyl, allyl, pyridyl, phenyl, pyrimidinyl, tetrazolyl, Represents a thiazolyl, diazolyl, quinolyl or furyl group; All alkenyl and alkenyl groups are halogen atoms, hydroxyl, at most 4 carbon atoms An alkoxy group containing trifluoromethyl, nitro, cyclohexyl, Lopentyl, pyridyl, pyrimidinyl, thienyl, tetrazolyl and phenyl groups May be substituted with one or more substituents selected from Alcohols containing halogen atoms, hydroxyl groups and at most 4 carbon atoms Substituted by one or more groups selected from a xy group, a cyano and a tetrazolyl group May be R_11BIs a hydrogen atom or R_10BRepresents the meaning defined for ) Represents a group of ・ R_4BRepresents a hydrogen atom, a linear or branched atom containing at most 6 carbon atoms. Alkyl or alkenyl groups, cyclohexyl, phenyl, pyridyl, pyrimidi Nil, tetrazolyl or imidazolyl group, all of which groups are --- halogen atom, --- hydroxyl, mercapto, acylthio, trifluoromethyl, trifluoro Rumethylthio, trifluoromethoxy, cyano, azide, nitro, formyl,- SO_ThreeH, free, salted, esterified or amidated Ruboxyl group, Alkyl, alkylthio, acyl, acyl containing at most 6 carbon atoms Oxy and alkoxy groups, phenyl and phenylthio groups (all of these groups are It itself contains a halogen atom, a hydroxyl group, an alkyl containing at most 4 carbon atoms. Oxy, free, salted, esterified or amidated Substituted by one or more groups selected from ruboxy, nitro and phenyl groups May be. ), --- isoxazolyl, pyrrolidinyl, pyrrolidinylcarbonyl, pyridyl, Limidyl, thiazolyl, diazolyl, piperidinyl, tetrazolyl, tetrahydrid Lofuranyl groups (all of these groups are substituted by methyl, ethyl or nitro groups) May be. ), −−Next formula (here,   R_6BAnd R_7BOr R_8BAnd R_9BMay be the same or different. An alkyl group containing at most 4 carbon atoms (halogen atom, hydroxy One or more groups selected from a group consisting of an alkoxy group and an alkoxy group containing at most 4 carbon atoms. It may be substituted by the same or different groups described above. ), Phenyl, benzyl , Phenethyl, azepine, piperidyl, morpholine, pyrrolidinyl, piperazini Selected from the group   On the other hand, R_6BAnd R_7B, On the other hand, R_8BAnd R_9BAre the nitrogen Together with the elementary atoms form a heterocyclic group, these identical or different groups being Groups: imidazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyridyl, piperidi Nil, pyrimidinyl, pyridazinyl, pyrazinyl, piperazinyl, phenylpipe Radinyl, piperidyl, oxazolyl, morpholinyl and thiomorpholinyl, Zepin, indolyl groups (these groups are halogen, hydroxyl, nitro, Cyano, acyl, trifluoromethyl groups, containing at most 4 carbon atoms Alkyl and alkoxy groups, free, salted, esterified or Select from imidized carboxy, tetrazolyl, oxazolyl and phenyl groups May be substituted by one or more identical or different groups. Selected from) Is) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y_BIs a phenyl group (halogen atom, dioxole group, cyano group, free, salt form Formed or esterified carboxy groups, tetrazolyl groups and Una- (CH_Two)_m3-S (O)_m2-X_B-R_10BOne or more groups selected from groups It may be more substituted. ). ] Of the formula [I_B) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_BInorganic) And corresponding to the addition salts with organic acids or with inorganic and organic bases of the above formula (I) The compound is in the application as described above.   -(CH_Two)_m3-S (O)_m2-X_B-R_10BThe group is, in particular, X_B-R_{Ten B} The group is: (Where n3 represents an integer of 0 to 3, and V is a single bond or -NH- and -O- And V₁And V_TwoSame or different, hydrogen atom, halogen An atom, especially a chlorine or bromine atom, an alkoxy group, especially a methoxy group,_FourIs A hydrogen atom or an alkyl or alkenyl group, especially methyl, ethyl, propyl, Represents butyl, vinyl or allyl. ) And a group representing the group of   Therefore,-(CH_Two)_m3-S (O)_m2-X_B-R_10BThe group is, for example, , A group represented by the following formula:   A further particular subject of the present invention is that 2 wherein Y together form a dioxol group. R and optionally substituted as described above._TwoAnd R_ThreeSelected from the meaning of Represents a phenyl group or a benzofuranyl group which may be substituted by one or more groups; The formula (I) corresponding to the above formula (I)_DA compound of the formula (I_D) In the form of all possible racemic, enantiomeric and diastereomeric isomers You. ] And formula (I_D) With inorganic and organic acids or with inorganic and organic bases In addition salts.   A very special subject of the invention is that of the formula (I)_C) [here,   R_1CIs hydroxy, linear or branched containing at most 12 carbon atoms Alkyl, alkoxy or alkylthio groups, formyl groups or dioxolane Or dioxane groups, all of which are hydroxyl, free, salt A formed, esterified or amidated carboxy group, at most Linear or branched alkoxy groups containing 4 carbon atoms and phenyl groups (such as Itself or a linear or branched alkyl group containing at most 4 carbon atoms. It may be substituted by a alkoxy group. By one or more groups selected from May be substituted,   R_2CAnd R_3CMay be the same or different, (A) halogen atoms, free, salted or at most 4 carbon atoms Carboxy or carboxy ester esterified by an alkyl group Bonyl group, formyl group, (B) The following equation       − (CH_Two)_m3-S (O)_m2-X_B-R_10B (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_B-R_10BRepresents an amino group, or   X_BIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11B-Represents a group,_10BIs at most 10 charcoals Linear or branched alkyl or alkenyl groups containing elemental atoms, the following groups: Pyridyl, phenyl, pyrimidinyl, tetrazolyl, thiazolyl, diazolyl, Represents a quinolyl or furyl group; these alkyl, alkenyl and phenyl groups All contain halogen atoms, hydroxyl groups, and at most 4 carbon atoms. Alkyl, alkenyl and alkoxy groups, free, salted or ester Carboxyl group, trifluoromethyl, nitro, cyclohexyl, cyclo Pentyl, pyridyl, pyrimidinyl, thienyl, tetrazolyl, morpholinyl and And may be substituted with one or more substituents selected from phenyl groups. In addition, all of the phenyl groups are dioxol, cyano, tetrazolyl, and at most four Alkyl and alkenyl groups containing carbon atoms (they are themselves carboxy groups) It may be substituted. ) Is substituted by one or more groups selected from Well, R_11BIs a hydrogen atom or R_10BRepresents the meaning defined for ) Of the (C) an alkyl or alkenyl group containing at most 4 carbon atoms, 6 Aryl, cycloalkyl containing up to carbon atoms and containing one or more heteroatoms Loalkyl or cycloalkenyl groups (these groups are directly linked to the imidazole ring Or a Q substituent (where Q is an oxygen or sulfur atom, or-(CH)_{n '}-,-( CH)_{n '}A -S- group (where n 'represents 1 to 4), -CH = CH-, It may be oxidized in the form of a phone. ). ), And All of these groups contain halogen atoms, hydroxyl groups and at most 4 carbon atoms. Containing alkoxy, cycloalkyl, free, salted or ester One or more selected from fluorinated carboxy, dioxol and phenyl groups Which may be substituted by dioxol, alkyl or Is an alkenyl group, which is itself free, salted or esterified It may be substituted by carboxy. By one or more groups selected from It may be substituted. ) Selected from   Y_CIs substituted by two groups which together form a dioxol group, and And optionally R_2CAnd R_3CSubstituted by one or more substituents selected from the meaning of Represents an optionally substituted phenyl group. ] Of the formula [I_C) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_CInorganic) And the above formula (I) corresponding to an addition salt with an organic acid or with an inorganic and organic base._D ).   The above formula (I_C), R_10B"Linear or branched alkyl represented by Alkenyl or alkenyl '' means, in particular, methyl, ethyl, linear or branched Propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ant And the like.   The above formula (I_C)), The "aryl group" is particularly phenyl, morpholinyl Or a tetrazolyl group.   Also, a special subject of the present invention is:   R_1CIs a linear or branched alkyl or alkyl containing at most 4 carbon atoms Is an alkoxy group (these groups are hydroxyl, alkoxy and phenyl) May be substituted by one or more groups selected from ), Dioxolane group Is an alkylthio group (linear or branched containing at most 12 carbon atoms) Alkyl group is a phenyl group (itself selected from halogen atoms and alkoxy groups) May be substituted by one or more of the following groups: May be replaced by No. )   (A) R_2CContains halogen atoms, formyl groups or at most 8 carbon atoms Linear or branched alkylthio or alkenylthio groups (hydroxyl group Or substituted by a free, salted or esterified carboxy group. It may be. ) Or   (B) R_2CIs a cyclohexyl, morpholinyl or phenyl group (these groups Are attached directly to the imidazole ring or by the Q substituent as described above, Cyclohexyl and phenyl groups are halogen atoms, the following groups: hydroxy and al A oxy, alkyl or alkenyl group (optionally substituted by a carboxy group . ) May be substituted with one or more groups selected from ) Or Or (Where Q is as described above, n1 represents a number of 1-4, and n2 is a number of 0-3 Represents a number, and n3 represents a number from 1 to 3. ) Represents a group of   R_3CIs the free, salted, esterified or amidated A boxy group, a sulfonylurea group, a free or salted tetrazolyl group or At most four are linear or branched alkyl or alkenyl groups (free, salt Formed, esterified or amidated carboxy group, tetrazo It may be substituted by a lyl or sulfonylurea group. )   Y_CIs substituted by two groups which together form a dioxol group, and Optionally halogen, hydroxy, alkoxy, free, salted Or carboxy or carboxycarbonyl groups esterified with Phenyl which may be substituted by one or more substituents selected from a razolyl group Represents a radical The above formula (I_C) Compound [This formula (I_C) Are all possible racemic, enane It can be in the form of thiomeric and diastereomeric isomers. ] And formula (I_C) In the addition salts of the compounds with inorganic and organic acids or with inorganic and organic bases.   A further special subject of the invention is:   R_1CIs a linear or branched methyl, ethyl, propyl or butyl group (hydr It may be substituted by a roxy or alkoxy group. ), Up to 6 carbons Selected from alkylthio groups containing atoms, dioxolane and dioxane groups,   R_2CBut   (A) The following equation (Where n4 represents a number of 2 or 3, and n2 and n3 have the above-mentioned meanings . ) Group, and   (B) alkylthio, alkenylthio, cycloalkylthio, cycloalkyl , Cycloalkylalkyl, cycloalkylalkenyl, phenyl, phenoxy , Phenylthio, benzyl, benzoyl, phenylthioalkyl groups (these groups Wherein the alkyl, alkenyl, cycloalkyl and phenyl groups are hydroxy , Carboxy, alkyl, alkenyl and alkoxy groups (the latter three are themselves It may be substituted by a carboxy group. By one or more groups selected from And the phenyl group may be a dioxol group having two adjacent carbons. May be substituted. ) Selected from   R_3CIs a free or esterified carboxy group, tetratetralyl or Selected from sulfonylurea groups,   Y_CIs replaced by two groups which together form a dioxol group, and Optionally selected from halogen, hydroxy, alkoxy and carboxy groups Represents a phenyl group optionally substituted by one or more groups The formula (I_C).   Among the compounds which are the subject of the present invention, in particular, the following formula: -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) methylthio) -1H-imidazole-5-carbo Acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -5-((4-methoxyphenyl) thio) -1H-imidazole-4- carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -2 , 4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imidazole -5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) thio) -2- (propylthio) -1H-imidazo Ole-5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((3,4-dimethoxyphenyl) thio) -2-propyl-1H-imidazo Ru-5-carboxylic acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4- (cyclohexylthio) -1H-imidazole-5-carboxylic acid , -2-butyl-4-((3-carboxypropyl) thio) -1-((6-chloro -1,3-benzodioxol-5-yl) methyl) -1H-imidazole-5 -Carboxylic acids, -4-(((4- (2-carboxyethyl) phenyl) thio) methyl) -1- ( (6-Chloro-1,3-benzodioxol-5-yl) methyl) -2-propy Ru-1H-imidazole-5-carboxylic acid, -4-((3-carboxypropyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid, -4-((7-carboxyheptyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid The above formula (I) corresponding to_C).   The formula (I_DCompounds of the formula (I) which do not correspond to) are, in particular, described in European patent application EPO , 465, 368 or 0, 503, 162. You.   The formula (I_D) And thus of the formula (I_C) Can be prepared as follows: You.   Thus, also, the subject of the present invention is a compound of formula (I_D)) Yes, this is ・ Formula (II) (Where R '₁Is R₁Has the meaning described above for any of its reactive functionalities The group may be protected by a protecting group. ) The compound of the following formula (III) (Where Hal represents a halogen atom and Y 'has the same meaning as described above for Y) However, any of the reactive functional groups may be protected by a protecting group. ) By reacting the compound of the following formula (IV₁) (Where R '₁And Y 'have the above-mentioned meaning. ) Of the formula (IV₁) Is subjected to a halogenation reaction to give the following formula (IV_Two) (Where R '₁, Hal and Y 'have the meaning given above. ) To obtain the compound of ・ Formula (VIII) (Here, Hal has the above-mentioned meaning.) Is reacted with a compound of formula (III) as described above, or a protecting group P is acted on. And the following equation (IX) (Where Hal has the above meaning and W is -CH_Two-Y '(Y' is as described above . ) Or P representing a protecting group for a nitrogen atom. ) And subjecting the compound of formula (IX) to a halogen-metal exchange reaction, The following formula (X), (X '), (XI), (XII) or (XII') (Where L₁And L '₁May be the same or different. Represents an alkyl, alkenyl or aryl group. ) With an electrophilic compound of the formula (XIII) (Where Hal and W have the above-mentioned meaning,₁Is aryl- or alk Ru-carbonyl, aryl- or alkyl-hydroxyalkyl or aryl A luthio group (where the aryl and the alkyl groups have the above-mentioned meanings, and May be protected by a protecting group. ). ) Of the formula (IV_Two) And (XIII) to one of the halogen atoms Subjected to a transmetalation reaction and then CO 2_TwoOr DMF or the following formula (V_a), (V_b), (VI_a), (VI_b) Or (VI_C) (Where Z₁Represents an optionally substituted alkyl, alkenyl or aryl group Wherein any of the reactive functional groups may be protected by a protecting group; k represents an alkyl group containing at most 4 carbon atoms. ) With an electrophilic compound of the following formula (I)₁) Or the following formula (XIV) (The above formula (I₁) And (XIV), R ′₁, R "₁, Hal, Y 'and W are as described above. Meaningful, Z_ThreeIs a carboxy group, a formyl group, SZ as described above.₁Or It has the following meaning. ). ) Of the formula (I)₁) Or (XIV)_ThreeIs formyl Represents an esterified carboxy group, these compounds have the following formula (VII)       Z_Two-SM (VII) (Where S represents a sulfur atom and M is gold such as sodium, potassium or copper Represents the genus, Z_TwoIs an optionally substituted alkyl, alkenyl or aryl group Wherein any of the reactive functional groups may be protected by a protecting group. ) And reacting the compound of the following formula (I_Two) Or the following formula (XV) (The above formula (I_Two) And (XV), R ′₁, R "₁, Y ', Z_TwoAnd W are as defined above. Has a taste, Z_FourRepresents a formyl group or an esterified carboxy group. ) Of the formula (I)_Two) And (XV)_FourIs a formyl group When represented, these compounds are subjected to an oxidation or reduction reaction to give the following formula (I_Three) Or the following formula (I_Four) (The above formula (I_Three) And (I_Four), R ′₁, R "₁, Z_Two, Y ′ and W are as defined above. Has a taste, Z_FiveIs CH_TwoOH groups or free or at most linear or branched Table 1 shows carboxy groups esterified by alkyl groups containing 6 carbon atoms I forgot. ) Of the formula (XV) or (I_Four)), W substitutes P as described above. When represented, the amine function blocked by P as described above is liberated. After the reaction, the compound of the formula (III) as described above is reacted to give the following formula (I)_Five) (Where R "₁And Y 'have the meaning given above, and R "_TwoAnd R "_ThreeOne of the above is Na Z_FourOr Z_FiveIndependently and SZ as described above_TwoRepresents ) To obtain the compound of ・ Next formula (XVI) (Where R '₁Has the meaning described above, and R ′_TwoAnd R '_ThreeIs R_TwoAnd R_ThreeAbout As defined above, but protected by a protecting group on any of its reactive functional groups. May be. ) Is reacted with a compound of the formula (III) as described above to give a compound of the following formula (I ′) (Where R '₁, R '_Two, R '_ThreeAnd Y 'have the above-mentioned meaning. ) Or a compound of ・ Formula (XVII) (Where R '₁Has the above-mentioned meaning. ) Oxidation reaction of the compound of the following formula (XVIII) (Where R '₁Has the meaning described above, and Z₆And Z₇One or both are free or Represents a steered carboxy group and, if appropriate, Z₆And Z₇The other is C The meaning of the N group is retained. ) And reacting a compound of formula (XVIII) with a compound of formula (III) as described above. And the following equation (I₆) (Where R '₁, Y ', Z₆And Z₇Has the above-mentioned meaning. ) To obtain the compound of   The resulting formula (I₁), (I_Two), (I_Three), (I_Four), (XIV), (XV), (I_Five), (I₆)as well as( I ′) can itself be a compound of formula (I), furthermore a compound of formula (I) or Is optionally and optionally added to a compound of the above formula to obtain another compound. The following conversion reaction: (A) an esterification reaction of an acid functional group, (B) a saponification reaction of the ester function to the acid function, (C) a conversion reaction of an ester function to an acyl function, (D) a conversion reaction of a cyano functional group to an acid functional group, (E) Conversion of the acid function to an amide function and then to an optional thioamide function reaction, (F) a reduction reaction of the carboxy function to the alcohol function, (G) Conversion reaction of alkoxy function to hydroxyl group or hydroxyl function Conversion reaction of to the alkoxy functional group, (H) oxidation reaction of alcohol function to aldehyde, acid or ketone function, (I) a conversion reaction of a formyl group to a carbamoyl group, (J) a conversion reaction of a carbamoyl group to a nitrile group, (K) a conversion reaction of a nitrile group to a tetrazolyl group, (L) conversion of an alkylthio or acylthio group to the corresponding sulfoxide or sulfone Oxidation reaction, (M) the corresponding sulfoximine of sulfide, sulfoxide or sulfone functionality Conversion reaction to (N) a conversion reaction of an oxo functional group to a thioxo functional group, Reaction (where L₁Is as described above. ), (P) The following formula of the acid functional group To a functional group, (Q) Conversion of β-ketosulfoxide function to α-ketothioester function , (R) the conversion of carbamates to ureas, especially the sulfonyl of sulfonyl carbamates Conversion reaction to urea, (S) conversion of the halogenated functionality to a formyl or esterified carboxy functionality Conversion reaction, (T) CH of formyl group_Two-CO_Twoalk or CH = CH-CO_Twoalk (where , Alk represents an alkyl group containing 1 to 4 carbon atoms. ) Followed by a conversion reaction to the corresponding acid, if appropriate (U) Formula of formyl group To a group of the formula Conversion to the group of (V) R '_TwoAnd R '_ThreeOptionally substituted alkyl or as described above for To a group, If it is S-Z_TwoConversion reaction (where alk and Z_TwoHas the above meaning . ), (X) elimination reaction of a protecting group that can be held by the protected reactive functional group, (Y) a salt-forming reaction to obtain the corresponding salts with an inorganic or organic acid or base, (Z) Resolution reaction of racemate to resolved product Characterized in that they are applied to one or more of the conversion reactions in any order. Thus, the compounds of the formula (I) obtained in this way have all the possible racemic, enantiomers It can be in the form of enantiomers and diastereomers.   Before continuing the synthesis according to the reaction shown in the above method, For certain starting materials and intermediates, converting one substituent to another It should be appreciated that such a conversion reaction can be performed for this purpose.   Under preferred conditions for practicing the present invention, the above method is performed in the following manner be able to. In the compound of the formula (III), the halogen atom is preferably a bromine atom. But also a chlorine or iodine atom. Formula (II) as described above , (VIII), (XVI), (XV) and (I_Four)) Imidazole compound of formula (XV) and (XV) I_FourIn the case of the compound of the formula (1), when W represents P, after deprotection of the nitrogen atom, ｝ Is condensed with the compound of the formula (III) as described above, and the compound of the formula (III) IV₁) And a compound of formula (IX) (when W represents Y '), a compound of formula (I_Five) And formula (I ′) The reaction for obtaining each of the compounds is carried out, for example, by using dimethylformamide or Tilacetamide, tetrahydrofuran, dimethoxyethane or dimethyls In a solvent such as sulfoxide, at the reflux temperature of the solvent or at ambient temperature, preferably It can be performed with stirring. The reaction is preferably carried out, for example, with sodium hydride. Or potassium, sodium or potassium carbonate, sodium or potassium Mumetilate, sodium or potassium ethylate, sodium Alternatively, the reaction is performed in the presence of a base such as potassium t-butyrate.   Formula (IV₁) Of the formula (IV_TwoThe halogenation reaction to the compound of Under the usual conditions known to the_TwoCl_TwoUse NBS in or in acetic acid And Br_TwoCan be performed.   Formula (IV_Two), (IX) and (XIII) are compounds of nBuLi or Et In an organometallic compound such as MgBr and a solvent such as THF, approximately -78 ° C (nB at ambient temperature (for EtMgBr) and at ambient temperature (for EtMgBr). Can undergo a halogen-metal exchange reaction on a halogen atom.   The formula (IV_Two) And the compound of formula (XIII), respectively.₁) And compounds of formula (XIV) CO to_TwoCarboxylation and formylation with DMF are Under normal conditions known to the human body, i.e. at ambient temperature in tetrahydrofuran Can be.   Z₁And Z_TwoMay be the same or different, and Z₁-S- and Z_Two-S- Is R_TwoAnd R_ThreeAlkyl, a, etc. having the corresponding meanings as described above for Denotes a alkenyl or aryl group, and any of the reactive functional groups are protected by a protecting group. It may be protected.   L₁And L '₁May be the same or different, and R "₁Is R₁Meaning Alkyl, alkenyl or aryl having a corresponding meaning selected from taste And any of its reactive functional groups may be protected by a protecting group. No.   Formula (IV_Two) Or (XIII) and a compound of formula (VI_a), (VI_b)or Is (VI_c)) And the corresponding formula (I)₁) Or (XIV) Reaction with EtMgBr at ambient temperature in tetrahydrofuran Can be performed in an equivalent manner.   Formula (IV_Two) And (XIII) with a compound of formula (V)_a) Or (V_bThe reaction with the compound of At normal temperature, e.g. in tetrahydrofuran at ambient temperature It can be carried out.   Compounds of formula (IX) and compounds of formulas (X), (X '), (XI), (XII) and (XII') The reaction is carried out under the usual conditions known to the person skilled in the art, i.e. Can be carried out at ambient temperature in the reactor.   Formula (XV) and Formula (I) as described above protected by P as described above._Four) Compound The amine function of can be liberated under normal conditions known to those skilled in the art, in particular where P is- CH_Two-O- (CH_Two)_Two-Si (CH_Three)_ThreeWhen representing a group, a hydrogen atom is Or in the presence of fluoride ions.   The saponification reaction is carried out by a usual method known to those skilled in the art, for example, methanol, ethanol, etc. Caustic soda in a solvent such as tanol, dioxane or dimethoxyethane Can be performed in the presence of potassium or cesium carbonate.   The formula (I_Two) And (XV)_Three) And formula (I_Four) To compounds Alternatively, the oxidation reaction can be performed by a usual method known to those skilled in the art.   R '₁, R "₁, R '_Two, R "_Two, R '_ThreeAnd R "_ThreeAccording to the meaning of formula (I)₁), (I_Two), ( I_Three), (I_Four), (I_Five), (I₆), (XIV), (IV_Two), (XV) and (I ') have the formula ( Constituting the compound of I) or one of the reactions (a) to (u) as described above or Conversion to other compounds of formula (I) by subjecting it to more than one reaction it can.   In this case, the various reactive agents which may be carried by certain compounds of the above reaction Functional groups can be protected if necessary. Those protecting groups are, for example, suitable Hydroxyl, acyl, free carboxy or amino groups which can be protected by various protecting groups. And monoalkylamino groups.   The following non-limiting examples of protection of reactive functional groups can be mentioned. A hydroxyl group is, for example, an alkyl group such as t-butyl, trimethylsilyl; , T-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, ben It can be protected by jyl or acetyl. An amino group is, for example, acetyl, trityl, benzyl, t-butoxycarbonyl; Phthalimide groups or other groups known from peptide chemistry be able to. -An acyl group such as a formyl group is, for example, dimethyl ketal or diethyl. Ketal, ethylenedioxyketal or diethylthioketal or ethyl In the form of a cyclic or acyclic ketal or thioketal, such as dithioketal. Can be protected. The acid function of the compound as described above, if desired, for example in methylene chloride, In the presence of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride Can be amidated with primary or secondary amines at ambient temperature. The acid function is, for example, an easily cleavable ester such as benzyl or t -Formed by butyl esters or esters known in the chemistry of peptides Can be protected in the form of an ester.   The formula (I₁), (I_Two), (I_Three), (I_Four), (I_Five), (IV_Two), (XIV), (XV) and (I ') Reactions that can be applied to the compound as desired or necessary, as described below, It can be carried out. (A) A compound as described above, if desired, is attached to a carboxy function which may be present. To carry out an esterification reaction. This is done according to the usual methods known to those skilled in the art. Can be performed. (B) an optional conversion reaction of the ester function of the compound to an acid function, Under normal conditions known to those skilled in the art, in particular, for example, alcohols such as methanol With caustic soda or caustic in coal medium or with hydrochloric acid or sulfuric acid It can be carried out by acid or alkali hydrolysis. Represents an optionally protected alkyl or aryl group. Against) , A hydrogen atom, the following groups: alkyl, alkylthioaryl, alkylsulfoxide , Aryl sulfoxide, alkyl sulfone, aryl sulfone, acyl, free Selected from salted, esterified or amidated carboxy These alkyl, alkylthio and aryl groups are substituted as described above. May be protected and protected. ) Can be performed .   Such a reaction may be carried out, for example, as described in the experimental section or by conventional methods known to those skilled in the art. Done by the method. (D) The possible cyano functionality of the compound as described above may be provided, if desired, to those skilled in the art. Under known normal conditions, for example, a mixture of sulfuric acid, glacial acetic acid and water (these three Are preferably in equal proportions. ) Or in caustic soda, such as Acid function by double hydrolysis performed under reflux in a mixture of ethanol and water Can be converted to (E) The conversion reaction of the acid function to the amide function is carried out, in particular, by the usual methods known to those skilled in the art. According to the conditions, for example SOCl_TwoTo form acid chloride, By amidation as described above, or by direct amidation of the above acids It can be carried out.   In particular, Are especially SOCCl in a solvent such as, for example, toluene or benzene._TwoAction The acid function is converted to the acid chloride by Can be obtained by reacting   The amide thus obtained is then, if desired, waxed, especially in toluene. It can be converted to thioamide by the action of Esson's reagent. (F) a free or esterified carboxy function which may be present on said compound Is reduced, if desired, to the alcohol function by conventional methods known to those skilled in the art. Can be Esterified carboxy functions, which may be present, may be By methods known to those skilled in the art, in particular, for example, tetrahydrofuran or dioxa. Lithium aluminum hydride in a solvent such as To an alcohol function.   Free carboxy groups which may be present in such compounds are, if desired, especially water It can be reduced to the alcohol function by boron iodide. (G) An alkoxy group which may be present, such as a methoxy group, of the aforementioned compound is preferably Then under normal conditions known to those skilled in the art, for example, a solvent such as methylene chloride With boron tribromide, with pyridine hydrobromide or hydrochloride or under reflux Hydroxylation with hydrobromic or hydrochloric acid in water or trifluoroacetic acid It can be converted to a functional group. (H) said possible alcohol function is, if desired, Oxidation under normal conditions, for example, to obtain aldehydes Activate the gun by operating the gun or by operating the Jones reagent to obtain the acid. It can be converted to a aldehyde or acid function. (I) and (j) conversion of formyl group to carbamoyl group and conversion of carbamoyl group The conversion reaction to the nitrile group is particularly effective for R_ThreeAnd R_FourFor the usual, known to those skilled in the art Under conditions, for example, via displacement with ketonitrile and amines (Che m. Comm. 1971, p. 733). (K) The nitrile functionality that may be present on the compounds described above, if desired, is known to those skilled in the art. For example, the following references: Kojima et al. Organome tric Chem.33, P. 337 (1971), as described in For example, metal azide such as sodium azide or trialkyl tin azide By cycloaddition to a functional group, it can be converted to a tetrazolyl group. (L) An alkylthio or arylthio group which may be present in the above compound is If desired, under ordinary conditions known to those skilled in the art, for example, peracetic acid or m-chloroperoxide By peracids such as benzoic acid or, for example, such as methylene chloride or dioxane Ozone, oxone, sodium periodate in the solvent at ambient temperature It can be converted to a rufoxide or sulfone function.   Sulfoxide functional groups can be used with compounds containing alkylthio or arylthio groups. It can be obtained by using an equimolar mixture with a reactant, especially a peracid.   Sulfone functionality is in excess with compounds containing alkylthio or arylthio groups. By using a mixture with a reactant, in particular with a peracid. (M) a sulfide, sulfoxide or sulfone function which may be present in the abovementioned compounds Is the corresponding sulfoximine function, if desired, under normal conditions known to those skilled in the art. Can be converted to a group. Examples of the preparation of compounds containing sulfoximine functional groups This will be described below, but is not limited thereto.   Thus, for example, compounds such as N- (arylsulfonyl) sulfoximine The aryl group represented by X 'is a toluene group For the production of this compound, this sulfoximine can be used, for example, in the following literature: C.I. R . Johnson et al. A. C. S.95, P. 4287 (1973) Thus, the corresponding sulfoxide, ie, -S (O) CH_ThreeP-toluenesulfo nitride Nil, preferably by acting in the presence of copper.   Other methods used are described, for example, in the following reference: Aktagawa et al. Org. Chem.49, P. 2282 (1984). Rusulfilimine (which itself converts from sulfoxide to the action of chloramine T, for example) Therefore, it is manufactured. ) Under conditions of phase transfer, for example, an acid such as sodium hypochlorite. Treatment with an agent. (N) The conversion reaction of the oxo functional group to the thioxo functional group is performed particularly with the Lowesson reagent. It can be carried out under the conditions described above. This can be done using manganese. Using sodium borohydride. (P) The conversion reaction of an acid function to a tetrazolylcarboxy function is carried out, for example, by acid The functional group is previously converted to the acid chloride as described above, and then the acid thus obtained is obtained. The chloride is treated with CuC≡N according to the usual conditions known to those skilled in the art. By the action By conversion to the group (Q) Conversion of β-ketosulfoxide function to α-ketothioester function Produces, for example, N-bromosuccinimide (NBS) in methylene chloride, for example. To the α-position of the ketosulfoxide, followed by the Pomerer reaction A mixture of trifluoroacetic acid and methylene chloride or a mixture of sulfuric acid and dioxane Can be accomplished by performing   In particular, as described in (c) and (q) above, the following reaction scheme is shown. Can be (In these compounds, R ′₁And Y 'have the above-mentioned meaning, and R is as described above. Represents an alkyl or aryl group which may be substituted. ) (R) the conversion of carbamates to ureas, especially the sulfonyl of sulfonyl carbamates The conversion to urea is carried out, for example, by using a solvent such as toluene in the presence of a suitable amine. It can be performed under reflux. (S) The conversion of the halogenated group to a formyl group is particularly attributable to organometallic induction in a solvent. It can be performed by acting a conductor, for example, ethyl magnesium bromide. . (T) CH = CH-CO of formyl group_TwoConversion to an alk group is a Wichig-type reaction By condensation of the appropriate phosphonium salt in the presence of more sodium hydride Can be. The conversion to the acid can be achieved by converting a base such as caustic soda in an alcoholic medium. This is done by the hydrolysis used. (U) Formula of formyl group Can be carried out by the Wittig reaction as described above. And next formula Is converted to a group by reduction using hydrogen in the presence of a catalyst, such as platinum oxide. Done. (V) CH of formyl group_TwoConversion to OH groups is carried out in ethanol at ambient temperature with a reducing agent. For example, using sodium borohydride. CH_TwoTo the Rs group The conversion is effected by the action of mesyl chloride in alcohol in the presence of Funich's base. Therefore, an appropriate Rs-SH thiol is allowed to act on the intermediate mesylate prepared in advance. Can be done by (W) Oxidation of the S-alk substituent to a sulfoxide is, for example, m-chloroperbenzoic acid. This can be done by the action of an acid. The conversion of thiols is, for example, trifluoro vinegar. It is achieved by a Pumella reaction in the presence of an acid anhydride. SZ of SH substituent_TwoTo the base Is converted to the halogenated derivative Hal-Z_TwoThe action of, for example, iodocyclohexane Can be achieved by   It was understood that the above reactions could be performed by conventional methods known to those skilled in the art. No. (X) Removal of protecting groups, such as those described above, can be accomplished by conventional methods known to those skilled in the art. Under conditions, especially hydrochloric acid, benzenesulfonic acid or p-toluenesulfonic acid, Or by acid hydrolysis carried out by an acid or an acid such as trifluoroacetic acid. It can also be carried out by catalytic hydrogenation.   The phthalimide group can be removed with hydrazine.   A list of the various protecting groups that can be used is given, for example, in French Patent BF 2,499,99. Found in No. 5. (Y) The compounds described above can, if desired, be prepared according to conventional methods known to those skilled in the art. For example, in a reaction using an inorganic or organic acid or an inorganic or organic base. Can be (Z) The optically active forms of the compounds described above are prepared according to the usual methods known to those skilled in the art. It can be produced by resolving the racemate.   Examples of such a reaction are shown, for example, in the following Production Examples.   The compounds of the formula (I) and their acid addition salts have valuable pharmacological properties. I do.   The compound of the formula (I) is provided with an antagonistic property to an endothelin receptor. Therefore, it is particularly induced by inhibitors of the effects of endothelin, especially by endothelin. It is an inhibitor of the emitted vasoconstrictive and hypertensive effects. In particular, the anti-ischemic effect is remarkable Yes, the vasoconstrictor activity of endothelin is eliminated.   Also, the compounds of formula (I) can be used at the level of all types of cells, especially smooth muscle cells, Can counteract the stimulatory effects of endothelin at the level of neuronal and bone cells it can.   Therefore, these properties justify their therapeutic use, and The subject of the invention is that Y is substituted by two groups which together form a dioxol group. And optionally R as described above._TwoAnd R_ThreeBy one or more groups selected from the meaning of At least one optionally substituted phenyl group or one benzofuranyl group; (I) corresponding to the above formula (I) also containing_DA compound of the formula (I_D) Is In all its possible racemic, enantiomeric and diastereomeric forms possible. ] And formula (I_D) With pharmaceutically acceptable inorganic and organic acids. Are in drugs consisting of addition salts with inorganic and organic bases.   Accordingly, the subject of the present invention is the above formula (I)_C) And formula (I_DA) a compound defined by [This formula (I_C) And formula (I_D) Are all possible racemic or optically active forms Could be. ] And formula (I_C) And formula (I_DA) a pharmaceutically acceptable inorganic and In drugs consisting of addition salts with organic acids or with inorganic and organic bases.   Also, a more specific subject of the present invention is the following formula (I)_C) [here,   R_1CIs hydroxy, linear or branched containing at most 12 carbon atoms Alkyl, alkoxy or alkylthio groups, formyl groups or dioxolane Or dioxane groups, all of which are hydroxyl, free, salt A formed, esterified or amidated carboxy group, at most Linear or branched alkoxy groups containing 4 carbon atoms and phenyl groups (such as Itself or a linear or branched alkyl group containing at most 4 carbon atoms. It may be substituted by a alkoxy group. By one or more groups selected from May be substituted,   R_2CAnd R_3CMay be the same or different, (A) halogen atoms, free, salted or at most 4 carbon atoms Carboxy or carboxy ester esterified by an alkyl group Bonyl group, formyl group, and (B) The following equation       − (CH_Two)_m3-S (O)_m2-X_B-R_10B (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_B-R_10BRepresents an amino group, or   X_BIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11B-Represents a group,_10BIs at most 10 charcoals Linear or branched alkyl or alkenyl groups containing elemental atoms, the following groups: Pyridyl, phenyl, pyrimidinyl, tetrazolyl, thiazolyl, diazolyl, Represents a quinolyl or furyl group; these alkyl, alkenyl and phenyl groups Are all halogen atoms, hydroxyl, alka containing at most 4 carbon atoms Coxy groups, free, salted or esterified carboxy groups, tri Fluoromethyl, nitro, cyclohexyl, cyclopentyl, pyridyl, pirimi Selected from dinyl, thienyl, tetrazolyl, morpholinyl and phenyl groups It may be substituted by one or more substituents, and all of the phenyl groups are Xyl, cyano, tetrazolyl, alkyl containing at most 4 carbon atoms And alkenyl groups (which may themselves be substituted by carboxy groups) or May be substituted by one or more groups selected from_11BIs a hydrogen atom or R_10BRepresents the meaning defined for ) Of the (C) an alkyl or alkenyl group containing at most 4 carbon atoms, 6 Aryl or aryl containing up to one carbon atom and containing one or more heteroatoms Are cycloalkyl groups (these groups are directly attached to the imidazole ring or Q substituents (here And Q is an oxygen or sulfur atom or-(CH)_{n '}-,-(CH)_{n '}-S- group (this Good. ). ) And all of these groups are halogen Atoms, hydroxyl groups, alkoxy groups containing at most 4 carbon atoms, Roalkyl, free, salted or esterified carboxy, dio May be substituted with one or more groups selected from xol and phenyl groups. Furthermore, these groups are dioxol, alkyl or alkenyl groups (these are themselves Is replaced by a free, salted or esterified carboxy May be. ) May be substituted with one or more groups selected from ) Selected from   Y_CIs substituted by two groups which together form a dioxol group, and And optionally R_2CAnd R_3CSubstituted by one or more substituents selected from the meaning of Represents an optionally substituted phenyl group. ] Of the formula [I_C) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_CInorganic) And the above formula (I) corresponding to an addition salt with an organic acid or with an inorganic and organic base._D )).   Furthermore, particular subjects of the invention are compounds described in the examples, in particular the following formulas: -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) methylthio) -1H-imidazole-5-carbo Acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4-((4-methoxyphenyl) thio) -1H-imidazole-5 carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -2 , 4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imidazole -5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) thio) -2- (propylthio) -1H-imidazo Ole-5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((3,4-dimethoxyphenyl) thio) -2-propyl-1H-imidazo Ru-5-carboxylic acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4- (cyclohexylthio) -1H-imidazole-5-carboxylic acid , -2-butyl-4-((3-carboxypropyl) thio) -1-((6-chloro -1,3-benzodioxol-5-yl) methyl) -1H-imidazole-5 -Carboxylic acids, -4-(((4- (2-carboxyethyl) phenyl) thio) methyl) -1- ( (6-Chloro-1,3-benzodioxol-5-yl) methyl) -2-propy Ru-1H-imidazole-5-carboxylic acid, -4-((3-carboxypropyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid, -4-((7-carboxyheptyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid, and -Addition of these with pharmaceutically acceptable inorganic and organic acids or with inorganic and organic bases. salt The formula (I_C).   The agents which are the subject of the present invention are useful, for example, in the treatment of any vasospasm, Used for treatment, coronary artery spasm, peripheral vasospasm, and for renal failure be able to. These drugs are also used in the treatment of myocardial infarction and congestive heart failure. Atherosclerosis and certain forms of hypertension to prevent recurrence of post-plastic stenosis Can be used to treat pressure, especially pulmonary arterial hypertension, as well as to treat asthma .   In addition, the agents of the present subject matter are useful in the treatment of osteoporosis, prostate hyperplasia and new Can be used as Ron protective agent.   The present invention also includes at least one of the above-mentioned drugs as an active ingredient. Pharmaceutical compositions.   Pharmaceutical compositions as described above may be administered orally, rectally, parenterally or dermally. Mucous membranes are topical for topical application or for intravenous or intramuscular injection. Can be administered more.   These pharmaceutical compositions may be solid or liquid and are commonly used as human medicine. In the form of tasteless or sugar-coated tablets, capsules, granules, suppositories, for injection It can be provided in the form of formulations, ointments, creams, gels and aerosol preparations. these Is prepared in the usual way. Active ingredients are commonly used in these pharmaceutical compositions Auxiliaries such as talc, gum arabic, lactose, starch, Gnesium, cocoa butter, aqueous or non-aqueous vehicles, animal or plant Fatty substances of physical properties, paraffin derivatives, glycols, various types of wet, dispersed or It can be blended with emulsifiers and preservatives.   Normal dosage will vary with the compound employed, the patient being treated and the illness, for example, May be 1 to 300 mg per day orally for humans, or intravenous route May be 1 to 100 mg per day.   Certain starting compounds of the formulas (II) and (XVI) are known, for example in Europe It can be manufactured as described in EP 0,168,950.   Other starting materials of the formulas (II) and (XVI) are described in particular in European Patent EP 0,46. 5,368 or as described in the experimental section below, especially in Examples 1 and 3. Can be manufactured.   Certain starting compounds of formulas (II) and (XVI) are commercial products, for example, The following substances of (II): -2-methoxymethylimidazole -2-propylimidazole -2-isopropylimidazole -2-ethylimidazole -2-methylimidazole Is so.   Examples of commercial products of the formula (XVI) are described in European Patent EP 0,465,368 or EP 0,503,162.   Also, certain compounds of the formulas (II) and (XVI) are, in particular, compounds of the formula (II) For example, one or more of the above-mentioned reactions (a) to (z) are performed under the above-mentioned conditions. It can also be manufactured by   Certain compounds of formula (XVI) may be obtained by monohalogenating the compound of formula (II). And the following equation (P₁) (Where R '₁And P have the meaning given for the compound of formula (II). ) And a compound of the formula (P₁) To a halogen-metal reaction known to those skilled in the art. Thus, after exchange, according to methods known to those skilled in the art, in particular, for example, of the formula (XIII) By the same type of reaction described above from the compound to the compound of formula (XIV), It can be obtained by reacting with an appropriate electrophilic compound.   Also, some of the compounds of formula (XVI) have the following reaction formula It can be manufactured according to   In addition, some of the compounds of formula (XVI) have the following reaction formula: It can be manufactured according to   Also, some of the compounds of formula (XVI) have the following reaction formula It can be manufactured according to   Starting compounds of formula (VIII) are commercially available, for example from Aldrich 2,4,5-tribromoimidazole or a conventional method known to those skilled in the art. Can be manufactured.   Equation (V_a), (V_b), (VI_a), (VI_b) And (IV_c) Starting materials are commercially available, especially Expression (V_a) Or the compound of (XI) -Sec-butyl disulfide -Ethyl disulfide -Isopropyl disulfide -Methyl disulfide -Benzyl disulfide -Phenyl disulfide -Propyl disulfide Expression (V_a) Or the compound of (XII) -Methyl methanethiosulfonate -Phenyl benzenethiosulfonate Expression (VI_a) Compound -Methyl chloroformate -Benzyl benzyl chloroformate -Isobutyl chloroformate -Ethyl chloroformate -N-propyl chloroformate Expression (VI_b) Compound -Dimethyl carbonate -Diethyl carbonate Expression (VI_c) Compound -Di-t-butyl oxalate -Diethyl oxalate -Dimethyl oxalate Is mentioned.   The starting compounds of the formulas (X), (X ') and (XII') are commercial products, in particular -The following compound of formula (X) -Benzaldehyde or butanal -The following compound of formula (X ') -Benzoyl or butyryl chloride -The following compound of formula (XII ') -Mesyl chloride -Tosyl chloride Is mentioned.   Some processes for the preparation of the compounds of the formula (III) are described in particular in European Patent EP 0,46. 5,368.   In addition, production examples of the compound of the formula (III) are described in the literature, and the examples are particularly No. 4,880,804 or for example in reference Chem. and Ind. No. 7, July 1987 (Howard and Cork Horn), p. 612-617 Is shown in   In particular, the compound of formula (III), which is 6-chloropiperonyl chloride, is Commercially available from   Finally, the subject of the present invention is a compound of formula (IV) as a new industrial compound₁), (IV_Two), (XI II), (XIV) and (XV) wherein Y 'is replaced by a dioxol group, and And optionally R_TwoAnd R_ThreeIs substituted by one or more substituents selected from the meaning of Represents an optionally substituted phenyl group, and its optional reactive functional group is protected by a protecting group. It may be. ).   Thus, a particular subject of the invention arises from aberrant stimulation of endothelin receptors Treatment of diseases, hypertension induced by endothelin, treatment of all vasospasm, Intended to treat cerebral hemorrhage, renal failure, myocardial infarction and prevent recurrence of stenosis after angioplasty. Formula (I) for the preparation of a pharmaceutical composition_C) And (I_D)).   The following examples are illustrative of the invention and do not limit the invention in any way. There is no.Example 1A : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) methylthio) -1H-imida Ethyl sol-5-carboxylateExample 1B : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -5-((4-methoxyphenyl) methylthio) -1H-imida Ethyl sol-4-carboxylateStep 1 : Ethyl ((butylcarbonyl) amino) cyanate   6.71 g of ethyl 2-cyano-2-aminoacetate (FI Logiman, G. Jau, Chem. and Ind. 1980, 541-542. Was. ) Is introduced into 100 ml of methylene chloride. Bring this solution to 0 ° C. . 24 ml of pyridine and then 6.31 ml of acid chloride at a temperature below 6 ° C. Add in 0 minutes.   The reaction medium is then returned to ambient temperature.   Toluene was added to remove excess pyridine and then 200 ml of methyl chloride Dissolve, wash twice with water and dry.   The solid obtained is purified by making it a paste in isopropyl ether. And then filtered. In this way, 8.40 g of the expected compound (white solid) is obtained. Was. Mp = 88 [deg.] C.analysis NMR, H, ppm, CDCl_Three   0.93 (+) J = 7CH _Three-CH_Two-CH_Two-CH_Two   1.37 (m); 1.66 (m) CH_Three− (CH _Two)_Two   1.37 (t) J = 7; 4.34 (m) CO_TwoEt   5.54 (d) J = 7.5 CH-CO   6.36 (wd) NH-COStep 2 : 3-amino-2-((butylcarbonyl) amino) -3-(((4-me Toxiphenyl) methyl) thio) ethyl propenoate   3 g of the compound obtained in step 1 above, 4 ml of p-methoxybenzyl mercapta , 0.2 ml of triethylamine and 5 ml of ethanol.   Stir at ambient temperature for 3-4 days, distill off the solvent and remove the residue with isopropyl ether And precipitate is filtered and washed thoroughly with isopropyl ether. this In this way, 4.65 g of the expected compound (white solid) was obtained. Mp = 120.degree.analysis IR, CHCl_Three(Cm^-1)   ＣC-NH ｛3448   = C-NH_Two       ｛3458, 3411, 3360   CO 1665 composite   C = C ｛1611   Aromatic $ 1592,1513   NH_Two             ｛1489 Trace analysis Step 3: 2-butyl-4-((4-methoxyphenyl) methylthio) -1H-i Ethyl midazole-5-carboxylate   The operation was started by introducing 1.14 g of phosphorus pentachloride into 20 ml of methylene chloride. The reaction medium was cooled to 0 ° C and 0.73 g of 4-dimethylaminopyridine was added to 7 ml of salt. A solution dissolved in methylene chloride is added. Then, stir for 5 minutes, then A solution obtained by dissolving 1 g of the compound obtained in the step 2 in 10 ml of methylene chloride Add slowly over 5 minutes.   Chromatography on silica using an EA / methylene chloride 10:90 mixture as eluent After torography, 686 mg of the expected compound was obtained. Mp = 105 [deg.] C.analysis IR, CHCl_Three(Cm^-1)   = C-NH @ 3435   + $ 3257   > = O max1672   Heterocycle ｛1610   + $ 1582   Aromatic # 1542, 1513, 1497   OCH_Three           Almost 2836Step 4 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) methylthio) -1H-imida Ethyl sol-5-carboxylate, and   2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -5-((4-methoxyphenyl) methylthio) -1H-imidazole -4-Ethyl carboxylate   495 mg of the compound obtained in step 3 above, 350 mg of 6-chloropipero chloride Nil and 235 mg of potassium bicarbonate with 14.2 ml of dimethylformamide. Mix at ambient temperature and leave the reaction medium for about 48 hours.   Then H_TwoHydrolysis with O (ammonium chloride) and then with ethyl acetate Extract and H_TwoO (ammonium chloride) twice, H_TwoTwice with O, then H_TwoO ( (Sodium chloride) twice, dried, filtered and evaporated to dryness.   Silica column using ethyl acetate / cyclohexane (1/4) as eluent 557.6 mg of the expected compound of Example 1A and 60.0 mg of Example 1B The expected compound was obtained.analysis 1) Compound of Example 1A White solid IR, CHCl_Three(Cm^-1)   = The absence of C-NH   > = O 1689   Aromatic $ 1611   + $ 1583   Heteroaromatic $ 1513,1503 2) Compound of Example 1B Oil IR, CHCl_Three(Cm^-1)   = The absence of C-NH   > = O 1708   Heterocycle ｛1610   + $ 1584   Aromatic ｛1512,1506,1484Example 2 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -4-((4-methoxyphenyl) methylthio) -1H-imidazo Ole-5-carboxylic acid   536 mg of the compound of Example 1A, followed by 1.04 ml of 2N sodium hydroxide solution and 1 0 ml of tetrahydrofuran is introduced into 10.4 ml of ethanol, and Heat at ° C for 12 hours.   Then, 10 ml of water (distillation) was added and the mixture was evaporated under vacuum to obtain After removing the solvent and ethanol, 20 ml of water (distillation) is added and the suspension is And 2.08 ml of hydrochloric acid (1N) are added dropwise, then the reaction medium is brought to ambient temperature. 1 hour with stirring, then 30 minutes under ultrasound and at 60 ° C. And leave it for one hour.   After cooling to ambient temperature, filter and then wash with distilled water (3 × 15 ml), 4 60 mg of the expected compound (white solid) were obtained. Mp = 158C.analysis IR, Nujol, cm^-1   > = O 1649   Aromatic $ 1615   + $ 1589   Heterocycle ｛1514,1502,1482 Trace analysis Example 3A: 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) thio) -1H-imidazole Ethyl-5-carboxylateExample 3B : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -5-((4-methoxyphenyl) thio) -1H-imidazole -4-Ethyl carboxylateStep 1 : 3-amino-2-((butylcarbonyl) amino) -3-((4-meth (Xyphenyl) thio) ethyl propenoate   1 g of the compound obtained in step 1 of example 1, 10 ml of 100% ethanol, 0.06 5cm^ThreeOf triethylamine and 1.72 ml of 4-methoxythiophenol Mix.   Stir for 3 hours at ambient temperature. The reaction medium is allowed to dry and 10 ml of isopropyl Dissolve in the water, stir for 30 minutes, separate, then rinse with isopropyl ether Go. 1.52 g of the expected compound (white solid) are obtained. Mp = 122 <0> C.analysis Trace analysis IR spectrum, CHCl_Three(Cm^-1)   ＣC-NH ｛3470   = C-NH_Two       $ 3415, 3370, 3290   > C = O ｛1660   NH_Two             ｛1593   + Amide II 1585   + Aromatic $ 1570   + C = C ｛1492 UV spectrum in ethanol   Max 235 nm ε = 13900   Max 290 nm ε = 28800Step 2 : 2-butyl-4-((4-methoxyphenyl) thio) -1H-imidazo Ethyl 5-carboxylate   1.75 g of phosphorus pentachloride and 87.5 ml of methylene chloride / NK₂₀Mix this Is cooled to -70 ° C and then 1.127 g of 4-dimethylaminopyridyl The solution is 11.27 ml of methylene chloride / NK.₂₀Solution added in 5 minutes I do.   Stir at −70 ° C. for 10 minutes, then add 1.48 g of the compound obtained in step 1 above 14.8 ml of methylene chloride / NK₂₀Is added over 5 minutes.   The reaction medium is returned to ambient temperature and stirred for 16 hours. 100ml sodium bicarbonate The hydrolysis is carried out by adding a saturated solution of sodium hydroxide and then stirring for 30 minutes. Cantated, re-extracted 3 times with 50 ml of methylene chloride, washed with 50 ml of water Clean and dry. Chromatography on silica using methylene chloride-ethyl acetate (8/2) After chromatography, 1 g of the expected compound (cream solid) was obtained. Mp = HO 96 ° C.analysis Trace analysis IR, CHCl_Three(Cm^-1)   = C-NH + association 3433   Composite C = O 1688   Heterocycle ｛1593   + $ 1572   + Aromatics 1543, 1519, 1494 UV spectrum ・ In ethanol (+ methylene chloride)   Infl 233 nm ε = 13100   Max 251 nm ε = 13800   Max 288 nm ε = 8800   Infl 225 nm ・ In ethanol-HCl (0.1N)   Max 242 nm ε = 16200   Max 273 nm ε = 8700   Infl 325 nmStep 3 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) thio) -1H-imidazole Ethyl-5-carboxylate, and   2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -5-((4-methoxyphenyl) thio) -1H-imidazole-4- Ethyl carboxylate   1.6 g of the compound obtained in step 2 above, 24 ml of dimethylformamide, From 0.79 g of sodium bicarbonate and 1.14 g of 6-chloropiperonyl chloride Starting off, the operation is carried out as in Example 1 and left at ambient temperature for 48 hours.   Clean on a silica column using methylene chloride-ethyl acetate 95-5 as eluent. After chromatography, 1.24 g of the expected compound of Example 3 (powder) (Mp = 10 0 ° C.) and 1.14 g of the expected compound of Example 3B (oil). 1) Compound of Example 3A IR, CHCl_Three(Cm^-1)   = The absence of C-NH   > = O 1691   Heterocycle ｛1627, 1594   + $ 1575   Aromatic ｛1505, 1494, 1483 2) Compound of Example 3B IR, CHCl_Three(Cm^-1)   = The absence of C-NH   > = O 1713   Heterocycle ｛1593, 1575   + $ 1505   Aromatic ｛1494Example 4 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -4-((4-methoxyphenyl) thio) -1H-imidazole- 5-carboxylic acid   0.35 g of the compound of Example 3A, 3 ml of ethanol and 1 ml of methanol Starting from the above, the procedure was as in Example 2, then 0.2 ml of 2N caustic The solution is introduced at ambient temperature.   The reaction medium is left at ambient temperature for 14 hours, allowed to dry and 10 ml of water, then 0.1 ml. Dissolve with 62 ml of 2N hydrochloric acid.   290 mg of the expected compound are thus obtained. Mp = 186.degree.analysis IR, Nujol (cm^-1)   General absorption OH / NH   -C = O 1685   Heterocycle ｛1590, 1570   + $ 1502 (F)   Aromatic $ 1490 (cp), 1480 (F) UV spectrum ・ In ethanol   Max 232 nm ε = 18100   Max 291 nm ε = 16500 ・ In acetic acid-NaOH (N10)   Max 241 nm ε = 18900   Max 285 nm ε = 1500 Trace analysis Example 5: 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -4-((4-methoxyphenyl) sulfinyl) -1H-imida Ethyl sol-5-carboxylate   0.4 g of the compound of Example 3A, 4 ml of methylene chloride / NK₂₀And 0.174 g of 85% m-chloroperbenzoic acid in 1.7 cm^ThreeMethylene chloride / N K₂₀Is added dropwise at 0 ° C.   The mixture was allowed to warm to ambient temperature and continued to stir for 4 hours, then a further 0.03 g of m-chloroperbenzoic acid in methylene chloride are added.   The reaction medium is stirred for 16 hours and then 50 cm^ThreePour into water and add 2ml bicarbonate The pH is adjusted to 6-7 by adding a saturated sodium solution, and 50 ml Extract three times with styrene.   The extract is dried, filtered and dried. Methylene chloride-ethyl acetate as eluent After purification by chromatography on a silica column using . 37 g of the expected compound (oil) are obtained.analysis IR, CHCl_Three(Cm^-1)   > = O 1711   Heterocycle ｛1595,1579   + $ 1528   Aromatic ｛1505,1495Example 6 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -4-((4-methoxyphenyl) sulfinyl) -1H-imida Sol-5-carboxylic acid   Starting by introducing 350 mg of the compound of Example 5 into 3.5 ml of ethanol Perform the operation as in Example 2. Then 0.438 ml of 2N caustic saw The solution is introduced and the reaction medium is left under stirring at ambient temperature for 4 hours. Let it dry The oily residue is dissolved in 5 ml of water, filtered and 0.44 ml of 2N hydrochloric acid is added And stir the whole for half an hour. After filtration, washing with water and drying, 287 mg of expected Compound was obtained. Mp = 90.degree.analysis IR, Nujol (cm^-1)   General absorption NH / OH   > C = O 1708   Heterocycle ｛1595,1580   + $ 1505   Aromatic $ 1496   S → O 1035 UV spectrum ・ In ethanol   Max 240 nm ε = 21000   Infl 260; 280; 295 nm Trace analysis Example 7: 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -5-((4-methoxyphenyl) thio) -1H-imidazole- 4-carboxylic acid   0.250 g of the compound of Example 3B is introduced into 2.5 ml of ethanol (10 volumes) And operate as in Example 2.   0.35 ml of 2N sodium hydroxide solution was introduced and the whole was stirred at ambient temperature for 14 hours. While leaving.   The reaction medium is evaporated to dryness, the residue is dissolved with 6 ml of water and then 0.35 ml of 2N hydrochloric acid is added with stirring.   In this way, 207 mg of the expected compound were obtained. Mp = 82 [deg.] C.analysis IR, CHCl_Three(Cm^-1)   General absorption OH / NH   > C = O 1700   Heterocycle ｛1595,1575   + $ 1525   Aromatic ｛1505,1494 Trace analysis Example 8: 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i M))-5-((4-methoxyphenyl) methylthio) -1H-imidazo Ole-4-carboxylic acid   Operating as in Example 7, starting from the compound of Example 1B, Compound was obtained.Example 9 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5-i L) methyl) -4-((4-methoxyphenyl) sulfonyl) -1H-imidazo Ethyl 5-carboxylate   0.44 g of the compound of Example 3A is introduced into 4.4 ml of methylene chloride and 0.39 A solution of 7 g of 85% m-chloroperbenzoic acid and 2 ml of methylene chloride was heated at ambient temperature. And dripping.   The reaction medium is stirred for 16 hours at ambient temperature, poured into 50 ml of water and mixed with sodium bicarbonate. To a pH of about 6-7 by addition of a saturated solution of sodium chloride and 50 ml of methylene chloride. Extract once, then dry, filter and dry.   Clean on a silica column using methylene chloride-ethyl acetate 95: 5 as eluent. After purification by chromatography, 380 mg of the expected compound were obtained.analysis IR, CHCl_Three(Cm^-1)   > = O 1714   -SO_Two− $ 1330,1149   Aromatic $ 1597   + $ 1580   Heterocycle ｛1506, 1499, 1485Example 10 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) sulfonyl) -1H-imida Sol-5-carboxylic acid   0.35 g of the compound of Example 9, 3.5 ml of ethanol and 0.43 ml of 2N The procedure is as in Example 2, starting from a sodium hydroxide solution.   The reaction medium is left under stirring at ambient temperature for 3 hours, allowed to dry and the residue is removed in an amount of 5 ml. Of water, add 0.44 ml of 2N hydrochloric acid and then stir the whole for 2 hours. And then filtered and washed with water.   In this way, 280 mg of the expected compound (powder) was obtained. Mp = 154 [deg.] C.analysis IR, CHCl_Three(Cm^-1)   > C = O 1730   Aromatic $ 1598,1581   + $ 1507   Heteroaromatic $ 1500 UV spectrum ・ In ethanol-hydrochloric acid (N / 10)   Max 245 nm ε = 19800   Infl 257; 270: 294 nm ・ In ethanol-caustic soda (N / 10)   Max 253 nm ε = 19800   Max 292 nm ε = 4200   Infl 270 nm Trace analysis Example 11: 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2,4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imida Sol-5-carboxaldehydeStep 1 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2,4,5-Tribromo-1H-imidazole   25 g of 2,4,5-tribromoimidazole was added to 500 ml of dimethylform. Introduce into the amide and add 4.3 g of sodium hydride. 10 minutes at ambient temperature Continue stirring. Then, 18.4 g of 6-chloropiperonyl chloride were added to the reaction medium. And then add 25 g of sodium iodide and stir at ambient temperature for 15 minutes.   Finally, the reaction medium is poured into 3 l of water, separated and then thoroughly washed with water, 250 ml of ethanol, then 250 ml of isopropanol and finally 25 Wash with 0 ml isopropyl ether.   After drying, 31.5 g of the expected compound (cream solid) was recovered. Mp = 225 ° C.analysis IR, CHCl_Three(Cm^-1)   = The absence of C-NH   Heterocycle + aromatic 1624-1506-1497-1485Step 2 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4,5-Dibromo-2- (phenylthio) -1H-imidazole   4.73 g of the compound obtained in the above step 1 was added to 100 ml of methylene chloride / sulfuric acid. Into the mixture (20/80), into which 3.5 ml of ethylmagnesium bromide were added. And the whole is kept stirring at ambient temperature for 30 minutes.   Next, 2.9 g of phenyl benzenethiosulfonate was introduced into the obtained reaction medium. Enter. Stir for 2 hours at ambient temperature.   The reaction medium is hydrolyzed by adding dilute hydrochloric acid, extracted with ethyl acetate, washed thoroughly with water. After drying, the cream-colored solid is recovered and is taken up in 50 ml of ethanol. And refine it by making it into a paste. Thus, the expected 3.35 g The compound was obtained. Mp = 165 [deg.] C.analysis IR, CHCl_Three(Cm^-1)   Heterocycle + aromatic 1585-1508-1484 Trace analysis Step 3: 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (phenylthio) -1H-imidazole-5-carboxa aldehyde   6.4 g of the compound obtained in the above step 2 was introduced into 100 ml of tetrahydrofuran. And 9.3 ml of ethyl magnesium bromide are added dropwise. 30 whole at ambient temperature Continue stirring for minutes.   Then, 5 equivalents of dimethylformamide are introduced into the reaction medium obtained.   Stir for 2 hours at ambient temperature.   The reaction medium is hydrolyzed by adding dilute hydrochloric acid, extracted with ethyl acetate, washed thoroughly with water. After drying, a brown solid was collected. Using this as eluent, methylene chloride And purified by chromatography on silica. 5g expected Compound was obtained. Mp = 155C. Reconstitute 500mg from 25ml ethanol Crystallize. After separation and drying, 420 mg of the expected compound (white solid) are recovered. Received. Mp = 155C.analysis IR, CHCl_Three(Cm^-1)   C = O 1669   Aromatic + heteroatom 1627-1580-1505-1485 Trace analysis Step 4: 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2,4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imida Sol-5-carboxaldehyde   620 mg of 50% sodium hydride in 50% oil in 50 ml of tetrahydrofuran And slowly add 1.8 ml of methoxybenzene methanethiol I do. Continue stirring at ambient temperature for 15 minutes.   The thiolate thus obtained was converted into the 3.8 g of the thiolate obtained in the above step 3. A solution obtained by dissolving the compound in 25 ml of tetrahydrofuran is added. these Continue stirring for 2 hours 30 minutes under the conditions.   Finally, the reaction medium is poured into a 0.1N sodium hydroxide solution, extracted with ethyl acetate, After washing with water and then drying, a brown resinous material was recovered. Use this as eluent 80 methylene chloride / cyclohexane 20, then methylene chloride + 20% ethyl acetate Purification by chromatography on silica using a silica gel.   Two fractions, 1.98 g of expected compound B and 1.97 formed under the same conditions g of the second compound A (Mp = 135 ° C.): 1-((6-chloro-1,3-benzoic acid) Dioxol-5-yl) methyl) -4-(((4-methoxyphenyl) methyl ) Thio) -2- (phenylthio) -1H-imidazole-5-carboxalde The hide was recovered.Analysis of Compound A IR, CHCl_Three(Cm^-1)   C = O 1660   Aromatic + heterocycle 1611-1580-1513-1505-1485 Trace analysis Analysis of Compound B IR, CHCl_Three(Cm^-1)   Absence of phenyl S   C = O 1655   Aromatic + heterocycle 1612-1585-1512-1508-1485Example 12 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2,4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imida Methyl sol-5-carboxylate   1 g of the compound of Example 11 is added to a methylene chloride / methanol mixture (50 ml / 100 ml), then 5 g of manganese oxide, 500 mg of sodium cyanide And 200 μl of acetic acid are added successively. Then stir at ambient temperature for 72 hours .   Separate, then wash with methylene chloride, concentrate and concentrate as eluent methylene chloride + Purify on silica using 20% ethyl acetate.   Thus, 750 mg of the expected compound (resin) was obtained.analysis IR, CHCl_Three(Cm^-1)   Ester 1696-1436   Aromatic + heterocyclic 1611-1580-1513-1505-1484Example 13 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2,4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imida Sol-5-carboxylic acid   Perform the operation as in Example 2. 580 mg of the compound of Example 12 was added to ethanol / It is introduced into a tetrahydrofuran mixture (20 ml / 60 ml), into which 20 ml Add 1N sodium hydroxide solution.   Stir for 48 hours at ambient temperature.   The reaction medium is acidified by addition of 2N hydrochloric acid, extracted with ethyl acetate and the extract is extracted with water. Wash, then dry and screen using methylene chloride + 5% methanol as eluent. Purify by chromatography on Rica.   Paste again in 50 ml of boiling ethanol and with 20 ml of ethyl acetate Purification is performed by washing and then drying, 350 mg of the expected compound (white Solid) was collected. Mp = 210C.analysis IR, Nujjol (cm^-1)   Composite absorption OH / NH   -C = O 1648   Heterocycle + aromatic 1613-1585-1513-1502 Trace analysis Example 14: 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (propylthio) -1H-imidazole-5-carboxa aldehydeStep 1 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4,5-dibromo-2- (propylthio) -1H-imidazole   5 g of the compound obtained in step 1 of example 11 are added to 100 ml of tetrahydrofuran Introduce.   The solution was cooled to -78 ° C, and 7.8 ml of methyl lithium was added thereto. Add well. Stir at this temperature for 10 minutes, then add 4 ml of dipropyldis Add sulfide. Continue stirring (at ambient temperature) for 2 hours 30 minutes.   The reaction medium is hydrolyzed by addition of dilute sodium hydroxide solution and 100 ml of ethanol And then separated, washed thoroughly with water and then with 150 ml of ethanol I do.   1.8 g of the expected compound (cream solid) was thus obtained. Mp = 1 16 ° C.analysis IR, CHCl_Three(Cm^-1)   Conjugated system 1627-1506-1484Step 2 : 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (propylthio) -1H-imidazole-5-carboxa aldehyde   2.1 g of the compound obtained in the above step 1 was introduced into 30 ml of tetrahydrofuran. And 10 ml of ethyl magnesium bromide are added dropwise. The reaction medium is kept at ambient temperature for 15 minutes. Stir for a minute.   Then, 2 ml of dimethylformamide are introduced into the reaction medium. 2 at ambient temperature Stir for hours.   The reaction medium is hydrolyzed by addition of dilute hydrochloric acid, extracted with ethyl acetate and then washed with water And dried and purified by pasting twice with 20 ml of ethanol .   In this way, 1.4 g of the expected compound were obtained. Mp = 145 [deg.] C.analysis IR, CHCl_Three(Cm^-1)   C = O 1663   Aromatic + heterocycle 1627-1505-1484Example 15 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2- (propylthio) -1H-i Midazole-5-carboxaldehyde   240 mg of 50% sodium hydride in oil in 50 ml of tetrahydrofuran And slowly add 0.6 ml of p-methoxyphenylthiol and add Stir at temperature for 15 minutes.   The thiolate thus formed was then combined with 1.4 g of the compound of Example 14 by 2 A solution of 0 ml of tetrahydrofuran is introduced and stirred for 2 hours. Next Then, the reaction medium was poured into 0.1N sodium hydroxide solution, extracted with ethyl acetate, and then extracted. Washed with water, dried and chromatographed on silica using methylene chloride as eluent. Purify by feeding. 1.32 g of the expected compound are thus obtained. .analysis IR, CHCl_Three(Cm^-1)   C = O 1657   Aromatic + heterocyclic ring 1593-1570-1505-1494-1484                       The S-Φ-OCH_Three Example 16 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2- (propylthio) -1H-i Midazole-5-carboxylate   The operation is performed as in Example 12. 1.26 g of the compound of Example 15 was converted into methyl chloride 6 g of manganese oxide introduced into a 20 ml / methanol mixture (20 ml / 100 ml). , 600 mg of sodium cyanide and 300 μl of acetic acid are added successively.   The stirring is then continued for 24 hours at ambient temperature.   In this way, 1.1 g of the expected compound are obtained.analysis IR, CHCl_Three(Cm^-1)   Ester 1697-1436   Aromatic and heterocyclic ring 1593-1575-1505-1494-1484Example 17 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2- (propylthio) -1H-i Midazole-5-carboxylic acid   Perform the operation as in Example 13. 1 g of the compound of Example 16 was added to ethanol / teto The mixture was introduced into a mixture of lahydrofuran (20 ml / 20 ml), and 25 ml of 1N Add caustic soda solution. Stir for 48 hours at ambient temperature.   In this way, 270 mg of the expected compound (white solid) was obtained. Mp = 164 ° C.analysis IR, Nujol (cm^-1)   -C = O 1650   Aromatic and heteroatoms 1592-1573-1508-1489 Trace analysis Example 18: 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-Brom-2-methyl-1H-imidazole-5-carboxaldehydeStep 1 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2-Methyl-1H-imidazole   12.3 g of 2-methyl-1H-imidazole, 7.92 g of 50% hydrogen in oil Sodium chloride, 150 mg of N-dimethylformamide and 33.8 g of chloride 6 Operating as in step 1 of example 11 starting from chlorpiperonyl.   The expected compound is obtained. This is used for the next step without isolation.Step 2 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4,5-Dibromo-2-methyl-1H-imidazole   The crude product obtained in Step 1 above was combined with 58.7 g of N-bromosuccinimide in 2 parts. It is introduced under reflux into a solution which is dissolved in 00 ml of methylene chloride.   In this way, 16.33 g of the expected compound was obtained. Mp = 185 [deg.] C.Step 3 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-Brom-2-methyl-1H-imidazole-5-carboxaldehyde   Dissolve 15 g of the compound obtained in step 2 above in 300 ml of tetrahydrofuran And 73.4 ml of a solution of ethyl magnesium bromide in tetrahydrofuran and 28 . As in step 3 of Example 11 using 4 ml of N-dimethylformamide Perform the operation.   In this way, 9.8 g of the expected compound are obtained. Mp = 141 <0> C.Example 19 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-methyl-1H-imidazole -5-carboxaldehyde   3 g of the compound of Example 18 are introduced into tetrahydrofuran and 765 mg of a 50% oil Starting from medium sodium hydride and 1.96 ml of 4-methoxythiophenol Then, operate as in step 4 of example 11.   Thus, 3.08 g of the expected compound (amorphous) was obtained.Example 20 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-methyl-1H-imidazole Methyl 5-carboxylate   1 g of the compound of Example 19, 5 g of manganese oxide, 500 mg of sodium cyanide System, 300 μl acetic acid, 100 cm^ThreeOf methanol and 20cm^ThreeMethylene chloride , And operate as in Example 12.   In this way, 410 mg of the expected compound are obtained. Mp = 152 [deg.] C.Example 21 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-methyl-1H-imidazo Le-5-carboxylic acid   740 mg of the compound of Example 12, 25 ml of 1N sodium hydroxide solution and 25 ml of The procedure is as in Example 13, starting from tanol.   In this way, 521 mg of the expected compound was obtained. Mp = 200-210 [deg.] C.Example 22 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-(((4-Methoxyphenyl) methyl) thio) -2-methyl-1H-i Midazole-5-carboxaldehyde   3 g of the compound of Example 18, 564 mg of 50% sodium hydride in 50% oil and 1.6 3 ml of 4-methoxybenzyl mercaptan are introduced into tetrahydrofuran, The operation is performed as in step 4 of 11.   Thus, 1.28 g of the expected compound (amorphous) was obtained.Example 23 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-(((4-Methoxyphenyl) methyl) thio) -2-methyl-1H-i Midazole-5-carboxylate   1.1 g of the compound of Example 22, 7 g of manganese oxide, 700 mg of sodium cyanide Li, 400 μl acetic acid, 100 ml methanol and 20 ml methyl chloride Starting from the operating point, operate as in Example 12.   In this way, 652 mg of the expected compound are obtained. Mp = 169C.Example 24 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-(((4-Methoxyphenyl) methyl) thio) -2-methyl-1H-i Midazole-5-carboxylic acid   489 mg of the compound of Example 23, 25 ml of 1N sodium hydroxide solution, 25 ml of ethanol Starting from ethanol and 40 ml of tetrahydrofuran, as in Example 13 Perform the operation.   In this way 310 mg of the expected compound are obtained. Mp = 190C.Example 25 : 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (α-hydroxy- (phenylmethyl))-1H-imida Sol-5-carboxaldehydeStep 1 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4,5-dibromo-α-phenyl-1H-imidazole-2-methanol   9.5 g of the compound obtained in step 1 of Example 11 are mixed with methylene chloride / sulphate ether (100 ml / 350 ml), and 7.3 ml of ethyl magnesium bromide was added. Drip. The whole is stirred for 20 minutes at ambient temperature.   Subsequently, 10 ml of benzaldehyde are introduced into the reaction medium obtained.   Stir for 2 hours at ambient temperature.   The reaction medium is hydrolyzed by adding dilute hydrochloric acid, extracted with ethyl acetate, and sufficiently washed with water. After drying, the cream-colored solid was recovered and added to 50 ml of ethanol. It is purified by making it into a paste.   In this way, 5.34 g of the expected compound are obtained.analysis IR, CHCl_Three(Cm^-1)   -OH 3603 + General absorption   Aromatic + heteroatom 1627-1603-1505-1484Step 2 : 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (α-hydroxy- (phenylmethyl))-1H-imida Sol-5-carboxaldehyde   5.3 g of the compound obtained in the above step 1 was introduced into 100 ml of tetrahydrofuran. And 11 ml of ethyl magnesium bromide are added dropwise. Mix at ambient temperature for 15 minutes. Stir for a minute.   Then 5 ml of dimethylformamide are introduced into the reaction medium obtained. Ambient temperature Stir for 2 hours.   The reaction medium is hydrolyzed by adding dilute hydrochloric acid, extracted with ethyl acetate, and sufficiently washed with water. After drying, a brown solid was recovered. Use this as eluent for methylene chloride Purification by chromatography on silica using   Thus, 2.067 g of the expected compound was obtained.analysis IR, CHCl_Three(Cm^-1)   C = O 1674   -OH 3596 composite   Aromatic + heterocyclic 1628-1602-1505-1485Example 26 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2- (α-Hydroxy- (phenylmethyl))-4-((4-methoxy Nyl) thio) -1H-imidazole-5-carboxaldehyde   The procedure is as in step 4 of example 11. 390 mg of 50% hydrogenated oil in oil Thorium was suspended in 50 ml of tetrahydrofuran, and 1 ml of methoxy was added thereto. Slowly add benzenethiol. Stir for 15 minutes at ambient temperature.   The thiolate thus formed was then combined with 2.6 g of the compound obtained in Example 25. Is dissolved in 25 ml of tetrahydrofuran. These conditions Continue stirring under 2 hours.   In this way, 2.15 g of the expected compound are obtained.analysis IR, CHCl_Three(Cm^-1)   C = O 1667   -OH 3598 Meeting   Aromatic + heterocyclic ring 1593-1574-1505-1494-1484Example 27 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2- (α-Hydroxy- (phenylmethyl))-4-((4-methoxy Nyl) thio) -1H-imidazole-5-carboxylate methylStep 1 : 2-benzoyl-1-((6-chloro-1,3-benzodioxole- 5-yl) methyl) -4-((4-methoxyphenyl) thio) -1H-imidazo Methyl 5-carboxylate   The operation is performed as in Example 12. 2.15 g of the compound obtained in example 26 ml of methanol, then 11 g of manganese oxide, 1.1 g of cyanide Add sodium and 700 μl acetic acid successively. Stir for 48 hours at ambient temperature You.   Working up as in Example 12, 1.32 g of the expected compound were obtained. Mp = 16 6 ° C.analysis IR, CHCl_Three(Cm^-1)   Absence of OH   C = O 1716-1653   Aromatic + heterocyclic ring 1597-1579-1508-1495Step 2 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2- (α-Hydroxy- (phenylmethyl))-4-((4-methoxy Nyl) thio) -1H-imidazole-5-carboxylate methyl   Add 820 mg of the compound obtained in step 1 above to 200 ml of ethanol. 65 mg of sodium borohydride are added to the suspension and the whole is left at ambient temperature for 2 hours. put. Ice is then added and the reaction medium is left at ambient temperature for 30 minutes, then Add 200 ml of water, filter, wash with water, wash with ethanol and dry. This As a result, 770 mg of the expected compound was obtained. Mp = 193C.Example 28 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2- (α-Hydroxy- (phenylmethyl))-4-((4-methoxy Nyl) thio) -1H-imidazole-5-carboxylic acid   Perform the operation as in Example 13. 760 mg of the compound of Example 27 was treated with acetic acid (50 ml) and tetrahydrofuran (50 ml). Of 1N sodium hydroxide solution is added and the whole is left at ambient temperature for 48 hours.   In this way, 660 mg of the expected compound were obtained. Mp = 130.degree.Example 29 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2- (1,3-dioxola -2-yl) -1H-imidazole-5-carboxaldehydeStep A : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4,5-Dibromo-2- (1,3-dioxolan-2-yl) -1H-imi Dazol   20 g of the compound obtained as in Example 11 are combined with 200 ml of dichloromethane And 15.6 ml of 3M ethyl bromide dissolved in 500 ml of ether. A solution of magnesium in ether is added and the whole is stirred for 20 minutes at ambient temperature. 2 Add 00 ml of 1N hydrochloric acid and extract with ethyl acetate. The organic phase is washed with water and dried Evaporate the solvent. Dissolve the obtained intermediate aldehyde in 200 ml of toluene And add 20 ml of ethylene glycol and heat to reflux for 16 hours. Solvent Evaporate, dissolve the residue in saturated aqueous sodium bicarbonate and extract with ethyl acetate And then washed with water, dried and the solvent is evaporated off under reduced pressure. Isopropyl residue Paste in ether, then filter, dry under reduced pressure and obtain 13.5 g of the expected The compound was collected. Mp = 188C.Step B : 4-bromo-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -2- (1,3-dioxolan-2-yl) -1H-imidazo Le-5-carboxaldehyde   10 g of the compound obtained in the above step A is introduced into 200 ml of tetrahydrofuran Then, 10 ml of a 3M solution of ethyl magnesium bromide in ether is added dropwise. Reaction medium Stir the body at ambient temperature for 20 minutes. Then, 10 ml of dye was added to the obtained reaction medium. Add tilformamide and stir at ambient temperature for 2 hours. 200 ml of reaction medium The mixture is hydrolyzed by adding dilute hydrochloric acid, extracted with ethyl acetate and then washed with water. After drying and pasting with isopropyl ether, 7.6 g of the expected compound is obtained. Was recovered. This is used for the next step as it is.Process C : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2- (1,3-dioxola -2-yl) -1H-imidazole-5-carboxaldehyde   3.15 ml of 3,4-dimethoxythiophenol was added to 200 ml of dimethylphos. 1.1 g of sodium hydride was added to the solution obtained by dissolving in Stir for 20 minutes at ambient temperature. Add 7.6 g of the compound obtained in step B above, Stirring is continued for 16 hours at ambient temperature, the solvent is evaporated off under reduced pressure and the residue is With saturated aqueous ammonium chloride solution and extracted with dichloromethane. Organic phase Is dried, the solvent is evaporated and the residue is pasted in isopropyl ether. Filtration gave 5.2 g of the expected compound. Mp = 149 [deg.] C.Example 30 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2- (1,3-dioxo Lan-2-yl) -1H-imidazole-5-carboxylate methyl   5.05 g of the compound of Example 29 was added to methylene chloride / methanol (100 ml / 50 0 ml) and then 22 g of manganese oxide, 2.2 g of sodium cyanide And 1.5 ml of acetic acid are added successively, then the whole is stirred at ambient temperature for 72 hours. I do. After filtration, the organic phase is washed with water, dried, evaporated and the chromatographed on silica. After torography, 4.1 g of the expected compound were obtained. Mp = 170.degree.Example 31 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2- (1,3-dioxola 2-Nyl) -1H-imidazole-5-carboxylic acid   1 g of the compound obtained in Example 30 is introduced into 100 ml of ethanol and 50 ml of 2 Add N sodium hydroxide solution. Stir at ambient temperature for 16 hours and evaporate the solvent under reduced pressure. And the residue is dissolved in an ice-cold water mixture, acidified with 2N hydrochloric acid and extracted with ethyl acetate And then dried and the solvent is evaporated off under reduced pressure. Collect 650mg of expected compound did. Mp = 155C.   Starting from the appropriate compounds, operating as described in Examples 29-31, The compound was prepared.Example 32 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-propyl-1H-imidazo Le-5-carboxylic acid   Mp = 174.5.degree.Example 33 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2- (1-methylethyl) -1H -Imidazole-5-carboxylic acid   Mp = 179C.Example 34 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2-propyl-1H-imi Dazol-5-carboxylic acid   Mp = 175 [deg.] C.Example 35 : 4- (butylthio) -1-((6-chloro-1,3-benzodioxo) Ru-5-yl) methyl) -2-propyl-1H-imidazole-5-carboxylic acid   Mp = 151.8 [deg.] C.Example 36 : 4-((2-carboxyphenyl) thio) -1-((6-chloro-1, 3-benzodioxol-5-yl) methyl) -2- (1-methylethyl) -1 H-imidazole-5-carboxylic acid   Mp = 203C.Example 37 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2- (1-Methylethyl) -4- (phenylthio) -1H-imidazole- 5-carboxylic acid   Rf = 0.2 (CH_TwoCl_Two-CH_ThreeOH95-5).Example 38 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((3,4-Dimethoxyphenyl) thio) -2- (1-hydroxy-1 -Methylethyl) -1H-imidazole-5-carboxylic acid potassium salt   The carboxylic acid obtained as above is dissolved in hot isopropanol and then A solution of potassium in isopropanol is added dropwise until a basic pH is obtained. At ambient temperature After stirring for 4 hours, the precipitate was separated and then isopropanol, isopropyl ether Wash with tel and dry to obtain the desired compound. Rf = 0.70 (AcOEt).   Starting from the appropriate compound, operating as in Example 4, the compound of the following example is Manufactured.Example 39 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylic acid   Mp = 177 [deg.] C.Example 40 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2-Ethyl-4-((4-methoxyphenyl) thio) -1H-imidazole -5-carboxylic acid   Mp = 172.degree.Example 41 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (Methylthio) -2-propyl-1H-imidazole-5-carboxyl acid   Mp = 196 [deg.] C.Example 42 : 4-((1,3-benzodioxol-5-yl) thio) -1-((6 -Chloro-1,3-benzodioxol-5-yl) methyl) -2-propyl- 1H-imidazole-5-carboxylic acid   Mp = 203C.Example 43 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -2-Propyl-1H-imidazole-4,5-dicarboxylic acid ethyl ester   2.54 g of 2-propyl-1H-imidazole-4,5-dicarboxylate Bio. Org. Med. Chem. Letters Vol. 1, p. 177-182 (produced as described in 1994)) in 50 ml of dimethyl Dissolved in chloroformate, 2.5 g of potassium carbonate, 2.5 g of 6-chlorochloride Piperonyl is added, followed by 2.5 g of sodium iodide. The resulting suspension was Heat at 0 ° C. for 1 hour, pour the reaction medium into ice-cold water, extract with ethyl acetate, Wash with water, dry, remove the solvent and chromatograph the residue on silica (solvent). Release agent: CH_TwoCl_Two-AcOEt80-20) to give 4.4 g of the expected compound. Rf = 0.36 (CH_TwoCl_Two-AcOEt80-20).Example 44 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-Formyl-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester   3.3 g of the compound obtained in Example 43 in -78 ° C in 40 ml of tetrahydrofuran And add 6.5 ml of diisobutylaluminum hydride and bring the whole to 2 hours. While stirring. The reaction medium is poured into a saturated aqueous solution of ammonium chloride and Extract, then wash with water, dry, remove the solvent and chromatograph the residue on silica. Fee (eluent: CH_TwoCl_Two-AcOEt 80-20) and 2.8 g of the expected compound I got something. Mp = 105 [deg.] C.Example 45 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (Hydroxymethyl) -2-propyl-1H-imidazole-5-ca Ethyl rubonate   Dissolve 2.1 g of the aldehyde obtained in Example 44 in 100 ml of ethanol and add 0 mg of sodium borohydride are added. Stir for 15 minutes at ambient temperature and remove acetic acid Addition to decompose excess reducing agent, remove solvent under reduced pressure, dissolve residue with water Basified with ammonium hydroxide, separated the precipitate, washed with water and reduced pressure Drying at 60 ° C. underneath gives 1.88 g of the expected compound. Mp = 114 [deg.] C.Example 46 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (Hydroxymethyl) -2-propyl-1H-imidazole-5-car Boric acid   500 mg of the compound obtained in Example 45 were combined with 25 ml of ethanol and 25 ml of caustic solution. Dissolve in the liquid. Stir at ambient temperature for 16 hours, remove the solvent under reduced pressure and remove the residue. Is dissolved in water, then filtered, acidified by adding 2N hydrochloric acid, the precipitate is separated off, Washing with water, washing with ethanol and drying under reduced pressure gave 380 mg of the expected compound. . Mp = 240.degree.   Starting from the aldehyde obtained in Example 44, operating as in Example 46, The following compound was obtained.Example 47 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-Formyl-2-propyl-1H-imidazole-5-carboxylic acidExample 48 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (cyclohexylthio) -1H-imidazole-5-car Ethyl borateStep A : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (methylsulfinyl) -1H-imidazole-5-car Ethyl borate   10 g of the ethyl ester obtained starting from the compound of Example 39 are mixed with 500 ml of dichloromethane. Dissolved in chloromethane, the solution was cooled to 0 ° C., and 6.6 g of m-chloroperbenzoic acid was added. The acid is added and then stirred for 2 hours 30 minutes. Reaction medium in sodium bicarbonate solution The organic phase was washed with water, dried, and the solvent was removed under reduced pressure. Evaporate down. 12 g of crude product were obtained. This is chromatographed on silica (Eluent: ethyl acetate-cyclohexane 7-3, then dichloromethane-medium) Tanol 85-15). 8.49 g of the expected compound are obtained. Mp = 103 [deg.] C.Step B : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (mercapto) -1H-imidazole-5-carboxylic acid Chill   1 g of the compound obtained in the above step A is dissolved in 20 ml of dichloromethane, 66 ml of trifluoroacetic anhydride are added. Stir for 30 minutes and remove solvent under reduced pressure And the residue is diluted with 10 ml of methanol and 4 ml of triethylamine. Dissolve and continue stirring at ambient temperature for 30 minutes, then extract with chloroform, The phases are washed with a saturated aqueous solution of ammonium chloride, dried and the solvent is evaporated off under reduced pressure. Let The obtained crude product was recrystallized from ether to obtain 490 mg of the desired compound. Was. Mp = 114 [deg.] C.Process C : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (cyclohexylthio) -1H-imidazole-5-car Ethyl borate   950 mg of the compound obtained in step B in 20 ml of dimethylformamide 125 mg of sodium hydride are added to the resulting solution. Then 0.33 ml Add iodocyclohexane and stir at ambient temperature for 3 hours. 20 ml of chloride Add saturated aqueous ammonium solution, extract with dichloromethane, wash with water and dry And the solvent is evaporated off under reduced pressure. Chromatography on silica (eluent: CH_Two Cl_Two) To give 850 mg of the expected compound. Rf = 0.43 (CH_TwoCl_Two).Example 49 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4- (cyclohexylthio) -1H-imidazole-5-car Boric acid   800 mg of the compound obtained in Example 48 was mixed with 50 ml of 2N sodium hydroxide solution and 50 ml And add tetrahydrofuran until complete dissolution is obtained. You. Stir for 48 hours at ambient temperature, evaporate the organic solvent under reduced pressure, and dilute the solution with 2N hydrochloric acid. Acidify to pH 1 using, separate the precipitate formed, wash with water and vacuum at 40 ° C After drying down and recrystallization from methanol, 317 mg of the expected compound are obtained. Mp = 257 ° C.   Starting from the appropriate compound and operating as described in Example 49, the compound of the following example Was manufactured.Example 50 : 2-butyl-4-((2-carboxyethenyl) thio) -1-((6- Chloro-1,3-benzodioxol-5-yl) methyl) -1H-imidazo Le-5-carboxylic acid   Mp = 212 [deg.] C.Example 51 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((1-methylethyl) thio) -1H-imidazole-5 -Carboxylic acid   Mp = 160.degree.Example 52 : 2-butyl-1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-hydroxybutyl) thio) -1H-imidazole -5-carboxylic acid   Mp = 135 [deg.] C.Example 53 : 2-butyl-4-((carboxymethyl) thio) -1-((6-chloro -1,3-benzodioxol-5-yl) methyl) -1H-imidazole-5 -Carboxylic acid   Mp = 165.8 ° C.Example 54 : 2-butyl-4-((3-carboxypropyl) thio) -1-((6- Chloro-1,3-benzodioxol-5-yl) methyl) -1H-imidazo Le-5-carboxylic acid   Mp = 140.degree.Example 55 : (E) 3- (1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-(((4-methoxyphenyl) thio) propyl-1H-i Ethyl midazol-5-yl) -2-propenoate   1.01 g of triethyl phosphonate, 15 ml of tetrahydrofuran and 17 Stir 2.8 mg of sodium hydride for 5 minutes at ambient temperature. Then, in Example 32 1 g of the aldehyde obtained during the synthesis of the compound in 30 ml of tetrahydrofuran Add the dissolved solution and continue stirring for 30 minutes. The solvent is evaporated under reduced pressure, The residue is dissolved in ethyl acetate, then washed with water, dried, evaporated and the crude The product is recrystallized at 40 ° C. from isopropyl ether. 1.16 g of the expected compound I got Mp = 167.8 ° C.Example 56 : (E) 3- (1-((6-chloro-1,3-benzodioxole-5- Yl) methyl) -4-((4-methoxyphenyl) thio) propyl-1H-imi Dazol-5-yl) -2-propenoic acid   850 mg of the compound obtained in Example 55, 40 ml of dicaustic soda solution and 40 ml Starting from ethanol, operating as in Example 49, stirring the reaction medium for 6 hours Leave with stirring. After recrystallization from isopropyl ether, Compound was obtained. Mp = 180.8C.Example 57 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-propyl-1H-imidazo Le-5-methyl acetateStep A : (Cis, trans) 1-((6-chloro-1,3-benzodioxo) Yl-5-yl) methyl) -4-((4-methoxyphenyl) thio) -5- (2 -Methylsulfinyl) -2- (methylthio) ethenyl) -2-propyl-1H -Imidazole   279 mg of methyl methylsulfinylmethylsulfoxide and 14 mg of caustic The sodium hydroxide is mixed and the mixture is stirred at 70 ° C. for 30 minutes, during the synthesis of the compound of Example 32 Is added in small portions. Stir at 70 ° C for 2 hours Subsequently, it is extracted with methylene chloride, then washed with water, dried and the solvent is evaporated off under reduced pressure. And the residue is chromatographed on silica (eluent: CH_TwoCl_Two-ACOEt4- 1) to give 617 mg of the expected compound.Step B : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-propyl-1H-imidazo Le-5-methyl acetate   Stir 1.02 ml of acetyl chloride in 4.1 ml of methanol for 15 minutes, Dissolve 380 mg of the compound obtained in step A in 2 ml of methanol. Add well. The reaction medium is acidified by addition of hydrochloric acid and at ambient temperature for 16 hours Stir and then neutralize by adding aqueous sodium bicarbonate. With dichloromethane Extract, wash the organic phase with water, dry, remove the solvent under reduced pressure and wash the residue with silica. Chromatography (eluent: CH_TwoCl_Two-ACOEt95-5), 290 mg The expected compound was obtained. Rf = 0.66 (eluent: CH_TwoCl_Two-ACOEt4-1).Example 58 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Methoxyphenyl) thio) -2-propyl-1H-imidazo Le-5-acetic acid   290 mg of the compound obtained in the above example, 10 cm^Three2N sodium hydroxide solution Liquid and 10cm^ThreeThe operation is carried out as in Example 49, using methanol. After recrystallization from ethyl acetate, 193 mg of the expected compound was obtained.   Mp = 187 [deg.] C.Example 59 : (E) 1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4- (2-phenylethenyl) -2-propyl-1H-imidazole Ethyl-5-carboxylate   1.2 g of benzyltriphenylphosphonium chloride in 30 ml of tetrahydro 150 mg of sodium hydride are added to the suspension contained in furan. 30 minutes The reaction medium is cooled to + 10 ° C. and the aldehyde of 1 g of Add the lahydrofuran solution and stir at ambient temperature for 2 hours, then filter and remove the organic phase. Was washed with tetrahydrofuran, the solvent was removed under reduced pressure and the residue was chromatographed on silica. Perform chromatography (eluent: CH_TwoCl_Two-AcOEt80-20). 920m g of the expected compound are obtained. Mp = 161 ° C.Example 60 : (E) 1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4- (2-phenylethenyl) -2-propyl-1H-imidazole -5-carboxylic acid   400 mg of the compound obtained in Example 59 was added to 50 ml of ethanol, 50 ml A solution of hydrofuran and 10 ml of 2N caustic soda solution at ambient temperature Stir for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in water, filtered, The mixture was acidified by adding 2N hydrochloric acid, and the precipitate was separated, washed with water, and then washed with ethanol. Purification and drying under reduced pressure at 50 ° C. yielded 250 mg of the expected compound. Mp = 2 30 ° C.Example 61 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (2-Phenylethyl) -2-propyl-1H-imidazole-5-ca Rubonic acid   490 mg of the compound obtained in Example 58 are mixed with 50 ml of ethanol and 50 ml of acetic acid. Dissolve in a mixture with chill, add 50 mg of platinum oxide and bring the whole to a pressure of 200 g Hydrogenate below. The catalyst is then separated, the solvent is removed under reduced pressure and the residue is Chromatography with mosquito (eluent: CH_TwoCl_Two-AcOEt95-5), 32 0 mg of 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (2-Phenylethyl) -2-propyl-1H-imidazole-5-ca Ethyl rubonate (Rf = 0.22 (CH_TwoCl_Two-AcOEt95-5)) and And 80 mg of the completely reduced product, 1-((6-chloro-1,3-benzene). Zodioxol-5-yl) methyl) -4- (2-cyclohexylethyl) -2 -Ethyl propyl-1H-imidazole-5-carboxylate (Rf = 0.35) Obtained.   300 mg of the partially reduced isomer is dissolved in 40 ml of ethanol and 5 ml of 2N sodium hydroxide solution are added and stirred at ambient temperature for 16 hours, then 2N hydrochloric acid And the solvent was removed under reduced pressure, the precipitate was separated, washed with water and After drying under reduced pressure and forming a paste in isopropyl ether, 240 mg The expected compound was obtained. Mp = 240.degree.   Starting from the appropriate compound, operating as described in Examples 59 and 60 Thus, the following esters and acids were prepared.Example 62 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4- (2-Cyclohexylethyl) -2-propyl-1H-imidazole- 5-carboxylic acid   Mp = approximately 150.degree.Example 63 : 4-(((4- (2-carboxyethyl) phenyl) thio) methyl)- 1-((6-chloro-1,3-benzodioxol-5-yl) methyl) -2- Ethyl propyl-1H-imidazole-5-carboxylate   500 mg of the compound obtained in Example 45 were dissolved in 50 ml of dichloromethane, and dissolved in 0.5 ml of dichloromethane. 8 ml of N-ethyldiisopropylamine are added. Cool the reaction medium to 0 ° C , 0.15 ml of mesyl chloride are added slowly, stirred for 1 hour and 360 mg of Add 4- (2-carboxyethyl) phenylthiol and continue stirring for 2 hours, It is then washed with water, dried, the solvent is removed under reduced pressure and the residue is chromatographed on silica. Fee (eluent: CH_TwoCl_Two-CH_ThreeOH95-5) 570mg expected The compound was obtained. Mp = 174.degree.Example 64 : 4-(((4- (2-carboxyethyl) phenyl) thio) methyl)- 1-((6-chloro-1,3-benzodioxol-5-yl) methyl) -2- Propyl-1H-imidazole-5-carboxylic acid   540 mg of the compound obtained in Example 63 are combined with 20 ml of ethanol and 10 ml of 2N. Dissolve in sodium hydroxide solution and stir the solution at ambient temperature for 5 hours. Solvent under reduced pressure Removed, filtered the aqueous phase, acidified it with acetic acid, separated the precipitate, washed with water, Dry at 50 ° C. under reduced pressure. Dissolve the residue in isopropyl ether, dry and , 420 mg of the expected compound were obtained. Mp = 171.degree.   Starting from the appropriate compound, the procedure is as described in Examples 63 and 64. Thus, the following esters and acids were prepared.Example 65 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-(((3,4-Dimethoxyphenyl) thio) methyl) -2-propyl- 1H-imidazole-5-carboxylic acid   Mp = 215C.Example 66 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-(((4- (1-Methylethyl) phenyl) thio) methyl) -2-pro Pill-1H-imidazole-5-carboxylic acid   Mp = 230 [deg.] C.Example 67 : 1-((6-chloro-1,3-benzodioxol-5-yl) methyl ) -4-((4-Morpholinyl) methyl) -2-propyl-1H-imidazole -5-carboxylic acid   Mp = 104 ° C.Example 68 : 1-((6-chloro-7- (1,2-dioxo-2-ethoxyethyl)) -1,3-benzodioxol-5-yl) methyl) -4-((3,4-dimethoate) (Xyphenyl) thio) -2-propyl-1H-imidazole-5-carboxylic acid   Dissolve 350 mg of the compound obtained in Example 34 in 30 ml of tetrahydrofuran, Cool the solution to -78 ° C and add 1.05 ml of n-butyllithium. 5 minutes And add 0.48 ml of diethyl oxalate and stir at ambient temperature for 1 hour. Subsequently, the reaction medium is hydrolyzed by addition of water, acidified by the addition of 2N hydrochloric acid and acetic acid. Extract with ethyl, wash the organic phase with water, dry, remove the solvent and wash the residue with silica. Chromatography (eluent: CH_TwoCl_Two-CH_ThreeOH95-5), 210 mg of the expected compound are obtained. Rf = 0.25 (CH_TwoCl_Two-CH_ThreeOH95-5) .Example 69 : 1-((6-chloro-7- (carboxycarbonyl) -1,3-benzo Dioxol-5-yl) methyl) -4-((3,4-dimethoxyphenyl) thio E) Potassium salt of 2-propyl-1H-imidazole-5-carboxylic acid   Solution obtained by dissolving 190 mg of the compound obtained in Example 68 in 10 ml of ethanol Add 5 ml of 2N sodium hydroxide solution to the mixture and stir at ambient temperature for 16 hours. Ethanor The aqueous phase was acidified by the addition of 2N hydrochloric acid and the precipitate was separated, Wash with water and dry under reduced pressure. The residue is dissolved in ethanol and 10 ml of caustic The solution is made alkaline by addition of a solution of And dried at 60 ° C. under reduced pressure. 70 mg of the expected compound are obtained. Mp> 260 ° C.   Starting from the appropriate compounds and operating as in Example 54, A compound was produced.Example 70 : 2-propyl-4-((3-carboxypropyl) thio) -1-((6 -Chloro-1,3-benzodioxol-5-yl) methyl) -1H-imidazo Ole-5-carboxylic acid   Mp = 154 [deg.] C.Example 71 : 2-propyl-4-((7-carboxyheptyl) thio) -1-((6 -Chloro-1,3-benzodioxol-5-yl) methyl) -1H-imidazo Ole-5-carboxylic acid   Mp = 133 [deg.] C.Example 72 : Examples of pharmaceutical compositions   A tablet having the following formulation was prepared.   Compound of Example 7: 50 mg   Auxiliary agent: amount required to make 200 mg per tablet (Details of adjuvant: lactose, talc, starch, magnesium stearate)Pharmacological results Study on the activity of endothelin on B receptor   Make a membrane preparation from rat posterior cortex + cerebellum. Tissues in Polytron 50 Triturate in mM Tris buffer (pH = 7.4).   After 30 minutes at 25 ° C. (WB), the homogenate is centrifuged at 30,000 G for 15 minutes. Centrifuge (collected in the middle in Tris buffer (pH = 7.4) and centrifuged twice ).   The pellet is incubated with incubation buffer (25 mM Tris, 5 μg / m 1 pepstatin A, 3 μg / ml aprotinin, 0.1 mM PMSF, 3 Resuspend in mM EDTA, 1 mM EGTA, pH = 7.4).   Dispense an aliquot of 2 ml into hemolysis tubes,¹²⁵I endothelin (almost 500 00 dpm / test tube) and the test compound. (The test compound is 3 × 10^-Five Test at M three times. ). The radioactivity at which the test compound specifically binds to the receptor When more than 50% were replaced, it was tested again according to a range of 7 concentrations The concentration which inhibits the radioactivity specifically bound to the receptor by 50% is determined. In this way, the 50% inhibition density is determined.   Non-specific binding is 10^-6Determined by adding M endothelin (3 times). Incubate at 25 ° C for 60 minutes and return to 0 ° C water bath for 5 minutes. After filtration under reduced pressure and rinsing with Tris buffer (pH = 7.4), the radioactivity was reduced. Count in the presence of scintillation triton.   The results are expressed as a 50% inhibitory concentration (IC50), ie, binding to the test receptor. Concentration of the test compound required to replace 50% of the specific activity (expressed in nM) ) Directly.result   The IC50s (nM) found for the compounds of the examples are shown in Table I below. Study on the activity of endothelin on A receptor   Make a membrane preparation from the rat heart (ventricle). 50m tissue in Polytron Triturate in M Tris buffer (pH = 7.4).   After 30 minutes at 25 ° C. (WB), the homogenate is centrifuged at 30,000 G for 15 minutes. Centrifuge (collected in the middle in Tris buffer (pH = 7.4) and centrifuged twice ).   The pellet is incubated with incubation buffer (25 mM Tris, 5 μg / m 1 pepstatin A, 3 μg / ml aprotinin, 0.1 mM PMSF, 3 Resuspend in mM EDTA, 1 mM EGTA, pH = 7.4).   Dispense an aliquot of 2 ml into hemolysis tubes,¹²⁵I endothelin (almost 500 00 dpm / test tube) and the test compound. (The test compound is 3 × 10^-Five Test at M three times. ). The radioactivity at which the test compound specifically binds to the receptor When more than 50% were replaced, it was tested again according to a range of 7 concentrations The concentration which inhibits the radioactivity specifically bound to the receptor by 50% is determined. In this way, the 50% inhibition density is determined.   Non-specific binding is 10^-6Determined by adding M endothelin (3 times). Incubate at 25 ° C for 60 minutes and return to 0 ° C water bath for 5 minutes. After filtration under reduced pressure and rinsing with Tris buffer (pH = 7.4), the radioactivity was reduced. Count in the presence of scintillation triton.   The results are expressed as a 50% inhibitory concentration (IC50), ie, binding to the test receptor. Concentration of the test compound required to replace 50% of the specific activity (expressed in nM) ) Directly.result   The IC50s (nM) found for the compounds of the examples are shown in Table II below.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/415 ABX A61K 31/415 ABX ACD ACD ACV ACV ADF ADF ADT ADT ADT

Claims (1)

[Claims] 1. The following formula (I) [here,   R₁Is hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alk A quinthio group (each of these groups is linear or branched; at most 12 Contains carbon atoms. ), Formyl group or cycloalkyl group (one or more hetero It may be interrupted by atoms and contains 3-7 carbon atoms. ) , All of these groups are halogen atoms, the following groups: hydroxyl, free, salt-forming Carboxyl groups, esterified or amidated, cyano, nitro Amino (one or two identical or containing at most 6 carbon atoms) It may be substituted by different alkyl groups. ) Containing from 3 to 7 carbon atoms Cycloalkyl, alkyl containing at most 6 carbon atoms, alkenyl And alkoxy groups, haloalkyl, alkylthio, haloalkylthio, haloa Lucoxy, phenoxy, phenylalkoxy, optionally substituted carbamoy , Acyl, acyloxy, tetrazolyl and phenyl which may be salted (Halogen, hydroxyl, alkyl containing at most 4 carbon atoms) And alkoxy groups, trifluoromethyl, cyano, free, salted and Is one or more selected from esterified carboxy and tetrazolyl groups May be substituted by a group. One or more same or different selected from May be substituted by a group,   R_TwoAnd R_ThreeMay be the same or different,   (A) halogen atoms, the following groups: mercapto, acyl, free, salted, Esterified or amidated carboxy or carboxycarbo Nil, nitro, cyano and -P (O) (OR)_TwoGroup (where R is a hydrogen atom, Represents an alkyl or phenyl group. ), And   (B) R_FourAnd -OR_FourBase {here, ・ R_FourIs       − (CH_Two)_m1-S (O)_m2-X-R_Ten (Where m1 represents an integer of 0 to 4, m2 represents an integer of 0 to 2,   X-R_TenRepresents an amino group, or   X is a single bond or -NR₁₁-, -NR₁₁-CO-, -NR₁₁-CO-O-, -N R₁₁-CO-NR₁₂-And -N = CR₁₁-NR₁₂-Represents a group and R_TenIs archi Represents an alkyl, alkenyl or aryl group, these groups being a halogen atom, the following groups: Hydroxyl, cycloalkyl containing from 7 to 7 carbon atoms, at most 6 Linear or branched alkyl, alkoxy, haloalkyl containing carbon atoms , Alkylthio, haloalkylthio and haloalkoxy groups, phenoxy, phenyl Alkoxy, optionally substituted carbamoyl, acyl, acyloxy, Isolated, salted or esterified carboxy groups, tetrazolyl, Ano, nitro, amino (one or two containing at most 6 carbon atoms) They may be substituted by the same or different alkyl groups. ) And aryl (Halogen, hydroxyl, alkyl containing at most 4 carbon atoms) And alkoxy groups, trifluoromethyl, free, salted or ester By one or more groups selected from carboxy groups and tetrazolyl groups It may be substituted. By one or more identical or different groups selected from May be substituted,   R₁₁And R₁₂May be the same or different, a hydrogen atom and R_TenAbout Selected from the defined meanings. ) Represents a group of ・ R_FourIs a hydrogen atom; alkyl, alkenyl, alkynyl and acyl groups (these are The radical is linear or branched, contains at most 6 carbon atoms, and contains sulfur, oxygen Or may be interrupted by one or more heteroatoms selected from nitrogen atoms. No. An amino or carbamoyl group (1 containing at most 6 carbon atoms) Or two identical or different alkyl or alkenyl groups or -(CH_Two)_m1-S (O)_m2-X-R_TenMay be substituted by a group . ) Represents a cycloalkyl group or an aryl group containing 3 to 6 carbon atoms. , R_FourAlkyl, alkenyl and aryl in all of the groups which may be represented by The group is A halogen atom, -Hydroxyl, mercapto, cyano, azide, nitro, -SO_ThreeH, free, A salted, esterified or amidated carboxy group, -The following groups: alkyl, alkenyl, alkoxy, haloalkyl, alkylthio, Alkenylthio, alkynylthio, acyl, acyloxy, acylthio, haloa Alkylthio, haloalkoxy groups (these groups contain at most 6 carbon atoms) You. ), Aryl, arylalkyl, arylalkenyl, arylthio, a Reeloxy and arylalkoxy groups (where the aryl group is a halogen atom, Hydroxyl groups, alkyl and alkoxy containing at most 6 carbon atoms, Haloalkyl, alkylthio, haloalkylthio, haloalkoxy, substituted Carbamoyl, acyl, acyloxy, free, salted or Are esterified carboxy, cyano, nitro, amino (at most 6 carbon Substituted by one or two identical or different alkyl groups containing atoms It may be. ), Tetrazolyl and phenyl (halogen atom, the following groups: Droxyl, alkyl and alkoxy containing at most 4 carbon atoms, tri Fluoromethyl, free, salted or esterified carboxy and And may be substituted with one or more groups selected from tetrazolyl and tetrazolyl. ) Or May be substituted by one or more same or different groups selected from ), as well as −Next equation (here,   R₆And R₇Or R₈And R₉May be the same or different, A hydrogen atom, -Amino acids, Alkyl and alkenyl groups containing at most 6 carbon atoms (halogen atoms Selected from a hydroxyl group or an alkoxy group containing at most 6 carbon atoms May be substituted by one or more identical or different groups. ), Aryl, arylalkyl and arylalkenyl groups, wherein the linear or Represents a branched alkyl and alkenyl group containing at most 6 carbon atoms, and These aryl, arylalkyl and arylalkenyl groups are halogen atoms , Hydroxyl, nitro, cyano, alkyl containing at most 6 carbon atoms Alkenyl, haloalkyl, alkoxy and acyl groups, amino groups (at most 6 To one or two identical or different alkyl groups containing two carbon atoms It may be more substituted. ), Free, salted or esterified Carboxyl, aryl and arylalkyl groups (the latter two groups being halogen Atom, hydroxyl, trifluoromethyl, nitro, cyano, free, salt-formed Selected from carboxyl and tetrazolyl groups, which have been substituted or esterified It may be substituted by more than one group. By one or more groups selected from It may be substituted. ),as well as -As described above-(CH_Two)_m1-S (O)_m2-X-R_TenBase Selected from, or   R₆And R₇Or R₈And R₉Together with the nitrogen atom to which they are attached A 5-, 6- or 7-membered monocyclic group or a group consisting of an 8- to 14-membered condensed ring (this The same or different groups may be one or more selected from oxygen, nitrogen and sulfur atoms. It may contain other heteroatoms, halogen atoms, hydroxy Nitro, cyano, alkyl, alkenyl containing at most 6 carbon atoms , Haloalkyl, alkoxy and acyl groups, amino groups (at most 6 carbon atoms) Substituted by one or two identical or different alkyl groups containing It may be. ), Free, salted, esterified or amide Carboxy, aryl and arylalkyl groups (the latter two groups being Rogen atom, hydroxyl, trifluoromethyl, nitro, cyano, free, salt Select from formed or esterified carboxy and tetrazolyl groups May be substituted by one or more of the following groups: One or more selected from May be substituted by a group. ) Or   R₈And R₉May be the same or different and represent an acyl group, or Is R₈Or R₉One is carbamoyl, alkoxycarbonyl or benzylo A carbonyl group and the other is R₈And R₉From the meaning defined above for Selected or R₈And R₉Together with the nitrogen atom to which they are attached To form a phthalimide or succinimide group. ) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y is the following equation     -Y₁-BY_Two ｛Here, Y₁Is an aryl group (a dioxol group and R_TwoAnd R_ThreeRepresented by It may be substituted by one or more groups selected from the groups obtained. )   B is Y₁And Y_TwoOr the following divalent group: —CO—, —O—, —NH—C O-, -CO-NH- or -O- (CH_Two)_p-(P represents a value of 1, 2 or 3 I forgot. )   Y_TwoIs: ・ The meaning of B and Y_TwoIs Y₁Whether or not the same as_TwoIs Y₁To Is selected from the meanings described above, or -When B represents a single bond, Y_TwoIs a hydrogen atom, a halogen atom, a cyano group, An isolated, salted, esterified or amidated carboxy group; A tetrazolyl group or-(CH_Two)_m1-S (O)_m2-X-R_TenTable Forget Is defined as ｝ Represents a group of ] [This compound of formula (I) has all possible racemic, enantiomeric and And diastereomeric isomers. And inorganic compounds of the formula (I) Of the endothelin receptor in addition salts with organic and organic acids or with inorganic and organic bases Use for the manufacture of a pharmaceutical composition intended for the treatment of diseases resulting from severe irritation. 2. Treatment of endothelin-induced hypertension, all vasospasm and brain Formula (I) according to claim 1 for preparing a pharmaceutical composition intended for treatment after bleeding. Uses of the compound. 3. Pharmaceutical composition intended to treat myocardial infarction and prevent recurrence of stenosis after angioplasty Use for manufacturing things. 4. The following equation (I_A) [here,   R_1AIs hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, a Alkylthio groups (each of these groups is linear or branched; at most 12 Containing carbon atoms. ), Formyl group, cyclo containing 3-7 carbon atoms Represents an alkyl group or a dioxolan or dioxane group; Is a halogen atom, a hydroxyl, an alkoxy containing at most 6 carbon atoms And alkylthio groups, acyl, free, salted, esterified and Are amidated carboxy, cyano, nitro, and amino groups (at most six One or two identical or different alkyl groups containing It may be replaced. A) a cycloalkyl group containing from 3 to 7 carbon atoms; Phenyl group (halogen, hydroxyl, containing at most 4 carbon atoms Alkyl and alkoxy groups, trifluoromethyl, free, salted Or selected from esterified carboxy, cyano and tetrazolyl groups It may be substituted by one or more groups. One or more identical or May be substituted by different groups,   R_2AAnd R_3AMay be the same or different,   (A) halogen, mercapto, acyl, free, salted or Sterilized carboxy or carboxycarbonyl, nitro, cyano group, And   (B) R_4AAnd -OR_4ABase {here, ・ R_4AIs       − (CH_Two)_m3-S (O)_m2-X_A-R_10A (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_A-R_10ARepresents an amino group, or   X_AIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11A-Represents a group and R_10AIs alkyl, alke Represents a phenyl or aryl group, which may be a halogen atom, a hydroxyl group, Alkyl and alkoxy groups containing at least 4 carbon atoms, trifluoromethyl Group, nitro group, cyclohexyl group, cyclopentyl group, aryl group (halogen Atoms, hydroxyl groups, alkyls and alcohols containing at most 6 carbon atoms Xy, trifluoromethyl, free, salted or esterified Carboxy, cyano, nitro, amino groups (containing at most 4 carbon atoms May be substituted by one or two same or different alkyl groups. No. ) May be substituted with one or more groups selected from Selected from) May be substituted with one or more substituents   R_11AIs a hydrogen atom or R_10ARepresents the meaning defined for ) Represents a group of ・ R_4AAre hydrogen, alkyl, alkenyl and acyl groups (these groups are linear or Are branched, contain at most 6 carbon atoms, and contain sulfur, oxygen or It may be interrupted by one or more heteroatoms selected from nitrogen atoms. ) An amino group (one or two identical or containing at most 6 carbon atoms) May be substituted by a different alkyl group. ) 3 to 6 carbon atoms Represents a cycloalkyl group or an aryl group,_4AGroup represented by In all of the alkyl, alkenyl and aryl groups are --- halogen atom, --- hydroxyl, mercapto, cyano, azide, nitro, SO_ThreeH, free, Salt-formed, esterified or amidated carboxy groups, --- alkyl, alkenyl, alkoxy, haloalkyl, alkylthio, acyl , Acyloxy, acylthio, haloalkylthio, haloalkoxy groups (these The groups contain at most 6 carbon atoms. ), Aryl, arylalkyl, a Reel alkenyl, arylthio, aryloxy and arylalkoxy groups ( Here, the aryl group has a halogen atom, a hydroxyl, and at most 6 carbon atoms. Containing alkyl and alkoxy groups, trifluoromethyl, free, salted Or esterified carboxy, cyano, nitro, amino groups (many and Also one or two identical or different alkyls containing four carbon atoms May be substituted by a group. ), Tetrazolyl group and phenyl group (halogen Atoms, hydroxyl groups, alkyls and alcohols containing at most 4 carbon atoms Xyl groups, trifluoromethyl and free, salted or esterified May be substituted by one or more groups selected from carboxy groups. ) Or May be substituted by one or more same or different groups selected from ), as well as −−Next formula (here,   R_6AAnd R_7AOr R_8AAnd R_9AMay be the same or different, A hydrogen atom, Alkyl groups containing at most 4 carbon atoms (halogen atoms, hydroxyl One or more selected from groups or alkoxy groups containing at most 4 carbon atoms May be substituted by the same or different groups. ), Aryl and arylalkyl groups, wherein the linear or branched alkyl groups Contains at most 4 carbon atoms and has the aryl and arylalkyl Is a halogen atom, hydroxyl, nitro, cyano, trifluoromethyl, Alkyl, alkoxy and acyl groups containing at most 6 carbon atoms, amino Groups (one or two identical or different containing at most 4 carbon atoms) May be substituted by an alkyl group. ), Free, salted or Esterified carboxy, tetrazolyl and phenyl groups (halogen atom, Droxyl, trifluoromethyl, nitro, cyano, free, salted, young Or one or more selected from esterified carboxy and tetrazolyl groups May be substituted by a group of Substituted with one or more groups selected from It may be. ) Selected from, or   R_6AAnd R_7AOr R_8AAnd R_9AIs one of the nitrogen atoms to which they are attached A group consisting of a 5-, 6- or 7-membered monocyclic group or an 8- to 14-membered fused ring ( These same or different groups may be one or more selected from oxygen, nitrogen and sulfur atoms. May contain other heteroatoms, halogen atoms, hydroxyl, Nitro, cyano and trifluoromethyl groups, containing at most 6 carbon atoms Alkyl, alkoxy and acyl groups, amino groups (containing at most 4 carbon atoms Substituted by one or two identical or different alkyl groups Is also good. ), Free, salted, esterified or amidated Carboxy, tetrazolyl, oxazolyl and phenyl groups (halogen atom, hydride Roxyl, trifluoromethyl, nitro, cyano, free, salted, young Is one or more selected from esterified carboxy and tetrazolyl groups May be substituted by a group. ) Is substituted by one or more groups selected from May be. ) Or   R_8AAnd R_9AMay be the same or different and represent an acyl group, or Iha R_8AOr R_9AOne of which is carbamoyl, alkoxycarbonyl or benzyl Represents a hydroxy group and the other is R_8AAnd R_9AThe meaning defined above for Selected from taste or R_8AAnd R_9AIs the same as the nitrogen atom to which they are attached. It forms a phthalimide or succinimide group. ) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y_AIs     -Y_1A-BY_2A ｛Here, Y_1AIs an aryl group (this is a dioxol group and R_2AAnd R_3ABy One or more groups selected from groups that may be represented may be more substituted. ) Represent,   B is Y_1AAnd Y_2AOr the following divalent group: —CO—, —O—, —NH— CO-, -CO-NH- or -O- (CH_Two)_p-(P is a value of 1, 2 or 3 Express. )   Y_2AIs: ・ The meaning of B and Y_2AIs Y_1AWhether or not the same as_2AIs Y_1A Is selected from the meaning described above, or -When B represents a single bond, Y_2AIs a hydrogen atom, a halogen atom, a cyano group, An isolated, salted, esterified or amidated carboxy group; A tetrazolyl group or-(CH_Two)_m3-S (O)_m2-X_A-R_10ABase Show Is defined as ｝ Represents a group of ] Of the formula [I_A) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_AInorganic) And corresponding to the addition salts with organic acids or with inorganic and organic bases of the above formula (I) The use according to claim 1 of the compound. 5. The following equation (I_B) [here,   R_1BIs a linear or branched alkyl containing at most 6 carbon atoms, Represents a oxy or alkylthio group, or a dioxolan or dioxane group All of these groups are halogen atoms, hydroxyl groups and at most six carbon atoms. Containing alkoxy and alkylthio groups, acyl, free, salted, Esterified or amidated carboxy, cyano, nitro, amino Groups (one or two identical or different containing at most 6 carbon atoms) May be substituted by such an alkyl group. ) Containing 3-7 carbon atoms Cycloalkyl and phenyl groups (halogen, hydroxyl, at most Alkyl and alkoxy groups containing 4 carbon atoms, trifluoromethyl, Isolated, salted or esterified carboxy groups, cyano and tetra It may be substituted by one or more groups selected from a zolyl group. Select from) May be substituted with one or more same or different groups,   R_2BAnd R_3BMay be the same or different,   (A) halogen atoms, mercapto groups, free, salted or ester Carboxy or carboxycarbonyl groups, hydroxyl groups, many Also include alkoxy and acyl groups containing 6 carbon atoms, cyano groups, nitro groups, Nzoyl group, and   (B) R_4BAnd -OR_4BBase {here, ・ R_4BIs       − (CH_Two)_m3-S (O)_m2-X_B-R_10B (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_B-R_10BRepresents an amino group, or   X_BIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11B-Represents a group,_10BIs methyl, ethyl, Ropyl, vinyl, allyl, pyridyl, phenyl, pyrimidinyl, tetrazolyl, Represents a thiazolyl, diazolyl, quinolyl or furyl group; All alkenyl and alkenyl groups are halogen atoms, hydroxyl, at most 4 carbon atoms An alkoxy group containing trifluoromethyl, nitro, cyclohexyl, Lopentyl, pyridyl, pyrimidinyl, thienyl, tetrazolyl and phenyl groups May be substituted with one or more substituents selected from Alcohols containing halogen atoms, hydroxyl groups and at most 4 carbon atoms Substituted by one or more groups selected from a xy group, a cyano and a tetrazolyl group May be R_11BIs a hydrogen atom or R_10BRepresents the meaning defined for ) Represents a group of ・ R_4BRepresents a hydrogen atom, a linear or branched atom containing at most 6 carbon atoms. Alkyl or alkenyl groups, cyclohexyl, phenyl, pyridyl, pyrimidi Nil, tetrazolyl or imidazolyl group, all of which groups are --- halogen atom, --- hydroxyl, mercapto, acylthio, trifluoromethyl, trifluoro Rumethylthio, trifluoromethoxy, cyano, azide, nitro, formyl,- SO_ThreeH, free, salted, esterified or amidated Ruboxyl group, Alkyl, alkylthio, acyl, acyl containing at most 6 carbon atoms Oxy and alkoxy groups, phenyl and phenylthio groups (all of these groups are It itself contains a halogen atom, a hydroxyl group, an alkyl containing at most 4 carbon atoms. Oxy, free, salted, esterified or amidated Substituted by one or more groups selected from ruboxy, nitro and phenyl groups May be. ), --- isoxazolyl, pyrrolidinyl, pyrrolidinylcarbonyl, pyridyl, Limidyl, thiazolyl, diazolyl, piperidinyl, tetrazolyl, tetrahydrid Lofuranyl groups (all of these groups are substituted by methyl, ethyl or nitro groups) May be. ), −−Next formula (here,   R_6BAnd R_7BOr R_8BAnd R_9BMay be the same or different. An alkyl group containing at most 4 carbon atoms (halogen atom, hydroxy One or more groups selected from a group consisting of an alkoxy group and an alkoxy group containing at most 4 carbon atoms. It may be substituted by the same or different groups described above. ), Phenyl, benzyl , Phenethyl, azepine, piperidyl, morpholine, pyrrolidinyl, piperazini Selected from the group   On the other hand, R_6BAnd R_7B, On the other hand, R_8BAnd R_9BAre the nitrogen Together with the elementary atoms form a heterocyclic group, these identical or different groups being Groups: imidazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyridyl, piperidi Nil, pyrimidinyl, pyridazinyl, pyrazinyl, piperazinyl, phenylpipe Radinyl, piperidyl, oxazolyl, morpholinyl and thiomorpholinyl, Sepin, indolyl groups (these groups are halogen, hydroxyl, nitro, Cyano, acyl, trifluoromethyl groups, containing at most 4 carbon atoms Alkyl and alkoxy groups, free, salted, esterified or Select from imidized carboxy, tetrazolyl, oxazolyl and phenyl groups May be substituted by one or more identical or different groups. Selected from) Is) Base And may be substituted by one or more same or different groups selected from ｝ Selected from   Y_BIs a phenyl group (halogen atom, dioxole group, cyano group, free, salt form Formed or esterified carboxy groups, tetrazolyl groups and Una- (CH_Two)_m2-S (O)_m2-X_B-R_10BOne or more groups selected from groups It may be more substituted. ). ] Of the formula [I_B) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_BInorganic) And corresponding to the addition salts with organic acids or with inorganic and organic bases of the above formula (I) The use according to any one of claims 1 or 4 for the compound. 6. Y is substituted by two groups which together form a dioxol group; Optionally, R as defined in claim 1_TwoAnd R_ThreeOne or more groups selected from the meaning of A phenyl group or a benzofuranyl group which may be more substituted. Formula (I) corresponding to the described formula (I)_DA compound of the formula (I_D) Is a compound of all It can be in the possible racemic, enantiomeric and diastereoisomeric forms. ] And formula (I_DAddition of compounds of formula (I) with inorganic and organic acids or with inorganic and organic bases salt. 7. The following equation (I_C) [here,   R_1CIs hydroxy, linear or branched containing at most 12 carbon atoms Alkyl, alkoxy or alkylthio groups, formyl groups or dioxolane Or dioxane groups, all of which are hydroxyl, free, salt A formed, esterified or amidated carboxy group, at most Linear or branched alkoxy groups containing 4 carbon atoms and phenyl groups (such as Itself or a linear or branched alkyl group containing at most 4 carbon atoms. It may be substituted by a alkoxy group. By one or more groups selected from May be substituted,   R_2CAnd R_3CMay be the same or different, (A) halogen atoms, free, salted or at most 4 carbon atoms Carboxy or carboxy ester esterified by an alkyl group Bonyl group, formyl group, (B) The following equation       − (CH_Two)_m3-S (O)_m2-X_B-R_10B (Where m3 represents an integer of 0 and 1, m2 represents an integer of 0 to 2,   X_B-R_10BRepresents an amino group, or   X_BIs a single bond or -NH-, -NHCO-, -NH-CO-O-, -NH-C O-NH- and -N = CH-NR_11B-Represents a group,_10BIs at most 10 charcoals Linear or branched alkyl or alkenyl groups containing elemental atoms, the following groups: Pyridyl, phenyl, pyrimidinyl, tetrazolyl, thiazolyl, diazolyl, Represents a quinolyl or furyl group; these alkyl, alkenyl and phenyl groups All contain halogen atoms, hydroxyl groups, and at most 4 carbon atoms. Alkyl, alkenyl and alkoxy groups, free, salted or ester Carboxyl group, trifluoromethyl, nitro, cyclohexyl, cyclo Pentyl, pyridyl, pyrimidinyl, thienyl, tetrazolyl, morpholinyl and And may be substituted with one or more substituents selected from phenyl groups. In addition, all of the phenyl groups are dioxol, cyano, tetrazolyl, and at most four Alkyl and alkenyl groups containing carbon atoms (they are themselves carboxy groups) It may be substituted. ) Is substituted by one or more groups selected from Well, R_11BIs a hydrogen atom or R_10BRepresents the meaning defined for ) Of the (C) an alkyl or alkenyl group containing at most 4 carbon atoms, 6 Aryl, cycloalkyl containing up to carbon atoms and containing one or more heteroatoms Loalkyl or cycloalkenyl groups (these groups are directly linked to the imidazole ring Or a Q substituent (where Q is an oxygen or sulfur atom, or-(CH)_{n '}-,-( CH)_{n '}A -S- group (where n 'represents 1 to 4), -CH = CH-, It may be oxidized in the form of a phone. ). ), And All of these groups contain halogen atoms, hydroxyl groups and at most 4 carbon atoms. Containing alkoxy, cycloalkyl, free, salted or ester One or more selected from fluorinated carboxy, dioxol and phenyl groups Which may be substituted by dioxol, alkyl or Is an alkenyl group, which is itself free, salted or esterified It may be substituted by carboxy. By one or more groups selected from It may be substituted. ) Selected from   Y_CIs substituted by two groups which together form a dioxol group, and And optionally R_2CAnd R_3CSubstituted by one or more substituents selected from the meaning of Represents an optionally substituted phenyl group. ] Of the formula [I_C) Are all possible racemic, enantiomeric and And diastereomeric isomers. ] And formula (I_CInorganic) 7. The formula according to claim 6, which corresponds to an addition salt with an organic acid or with an inorganic and organic base. (I_DAddition salts of the compounds of formula (I) with inorganic and organic acids or with inorganic and organic bases. 8. R_1CIs a linear or branched alkyl radical containing at most 4 carbon atoms Or alkoxy groups (these groups are hydroxyl, alkoxy and phenyl It may be substituted by one or more groups selected from groups. ), Dioxolan Groups or alkylthio groups, linear or containing at most 12 carbon atoms A branched alkyl group is a phenyl group (which itself is It may be substituted by one or more selected groups. ) Is also good. )   (A) R_2CContains halogen atoms, formyl groups or at most 8 carbon atoms Linear or branched alkylthio or alkenylthio groups (hydroxyl group Or substituted by a free, salted or esterified carboxy group. It may be. ) Or   (B) R_2CIs a cyclohexyl, morpholinyl or phenyl group (these groups Are attached directly to the imidazole ring or by the Q substituent as described above, Cyclohexyl and phenyl groups are halogen atoms, the following groups: hydroxy and al A oxy, alkyl or alkenyl group (optionally substituted by a carboxy group . ) May be substituted with one or more groups selected from ) Or Or (Where Q is as described above, n1 represents a number of 1-4, and n2 is a number of 0-3 Represents a number, and n3 represents a number from 1 to 3. ) Represents a group of   R_3cIs the free, salted, esterified or amidated A boxy group, a sulfonylurea group, a free or salted tetrazolyl group or At most four are linear or branched alkyl or alkenyl groups (free, salt Formed, esterified or amidated carboxy group, tetrazo It may be substituted by a lyl or sulfonylurea group. )   Y_CIs substituted by two groups which together form a dioxol group, and Optionally halogen, hydroxy, alkoxy, free, salted Or carboxy or carboxycarbonyl groups esterified with Phenyl which may be substituted by one or more substituents selected from a razolyl group Represents a radical The formula (I) according to claim 7_C) Compound [This formula (I_C) Is a compound of all possible race It can be in the form of mi, enantiomers and diastereoisomers. ] And formula (I_CAddition salts of the compounds of formula (I) with inorganic and organic acids or with inorganic and organic bases. 9. R_1cIs a linear or branched methyl, ethyl, propyl or butyl group ( It may be substituted by a hydroxy or alkoxy group. ), Up to 6 Selected from alkylthio, dioxolane and dioxane groups containing carbon atoms. And   R_2cBut   (A) The following equation (Where n4 represents a number of 2 or 3, and n2 and n3 are the meanings of claim 8) Having. ) Group, and   (B) alkylthio, alkenylthio, cycloalkylthio, cycloalkyl , Cycloalkylalkyl, cycloalkylalkenyl, phenyl, phenoxy , Phenylthio, benzyl, benzoyl, phenylthioalkyl groups (these groups Wherein the alkyl, alkenyl, cycloalkyl and phenyl groups are hydroxy , Carboxy, alkyl, alkenyl and alkoxy groups (the latter three are themselves It may be substituted by a carboxy group. By one or more groups selected from And the phenyl group may be a dioxol group having two adjacent carbons. May be substituted. ) Selected from   R_3CIs a free or esterified carboxy group, tetratetralyl or Selected from sulfonylurea groups,   Y_CIs replaced by two groups which together form a dioxol group, and Optionally selected from halogen, hydroxy, alkoxy and carboxy groups Represents a phenyl group optionally substituted by one or more groups The formula (I) according to claim 8_C). 10. The following formula: -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) methylthio) -1H-imidazole-5-carbo Acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -5-((4-methoxyphenyl) thio) -1H-imidazole-4- carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -2 , 4-Bis (((4-methoxyphenyl) methyl) thio) -1H-imidazole -5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((4-methoxyphenyl) thio) -2- (propylthio) -1H-imidazo Ole-5-carboxylic acid, -1-((6-Chloro-1,3-benzodioxol-5-yl) methyl) -4 -((3,4-dimethoxyphenyl) thio) -2-propyl-1H-imidazo Ru-5-carboxylic acid, -2-butyl-1-((6-chloro-1,3-benzodioxol-5-yl) Methyl) -4- (cyclohexylthio) -1H-imidazole-5-carboxylic acid , -2-butyl-4-((3-carboxypropyl) thio) -1-((6-chloro -1,3-benzodioxol-5-yl) methyl) -1H-imidazole-5 -Carboxylic acids, -4-(((4- (2-carboxyethyl) phenyl) thio) methyl) -1- ( (6-Chloro-1,3-benzodioxol-5-yl) methyl) -2-propy Ru-1H-imidazole-5-carboxylic acid, -4-((3-carboxypropyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid, -4-((7-carboxyheptyl) thio) -1-((6-chloro-1,3-be (Nzodioxol-5-yl) methyl) -2-propyl-1H-imidazole- 5-carboxylic acid The formula (I) according to any one of claims 7 to 9, which corresponds to_C). 11. The formula (I) according to claim 6_DIn producing the compound and the addition salt of ・ Formula (II) (Where R '₁Is R₁Has the meaning described above for any of its reactive functionalities The group may be protected by a protecting group. ) The compound of the following formula (III) (Where Hal represents a halogen atom and Y 'has the same meaning as described above for Y) However, any of the reactive functional groups may be protected by a protecting group. ) By reacting the compound of the following formula (IV₁) (Where R '₁And Y 'have the above-mentioned meaning. ) Of the formula (IV₁) Is subjected to a halogenation reaction to give the following formula (IV_Two) (Where R '₁, Hal and Y 'have the meaning given above. ) To obtain the compound of ・ Formula (VIII) (Here, Hal has the above-mentioned meaning.) Is reacted with a compound of formula (III) as described above, or a protecting group P is acted on. And the following equation (IX) (Where Hal has the above meaning and W is -CH_Two-Y '(Y' is as described above . ) Or P representing a protecting group for a nitrogen atom. ) And subjecting the compound of formula (IX) to a halogen-metal exchange reaction, The following formula (X), (X '), (XI), (XII) or (XII') (Where L₁And L '₁May be the same or different. Represents an alkyl, alkenyl or aryl group. ) With an electrophilic compound of the formula (XIII) (Where Hal and W have the above-mentioned meaning,₁Is aryl- or alk Ru-carbonyl, aryl- or alkyl-hydroxyalkyl or aryl A luthio group (where the aryl and the alkyl groups have the above-mentioned meanings, and May be protected by a protecting group. ). ) Of the formula (IV_Two) And (XIII) to one of the halogen atoms Subjected to a transmetalation reaction and then CO 2_TwoOr DMF or the following formula (V_a), (V_b), (VI_a), (VI_b) Or (VI_c) (Where Z₁Represents an optionally substituted alkyl, alkenyl or aryl group Wherein any of the reactive functional groups may be protected by a protecting group; k represents an alkyl group containing at most 4 carbon atoms. ) With an electrophilic compound of the following formula (I)₁) Or the following formula (XIV) (The above formula (I₁) And (XIV), R ′₁, R "₁, Hal, Y 'and W are as described above. Meaningful, Z_ThreeIs a carboxy group, a formyl group, SZ as described above.₁Or It has the following meaning. ). ) Of the formula (I)₁) Or (XIV)_ThreeIs formyl Represents an esterified carboxy group, these compounds have the following formula (VII)       Z_Two-SM (VII) (Where S represents a sulfur atom and M is gold such as sodium, potassium or copper Represents the genus, Z_TwoIs an optionally substituted alkyl, alkenyl or aryl group Wherein any of the reactive functional groups may be protected by a protecting group. ) And reacting the compound of the following formula (I_Two) Or the following formula (XV) (The above formula (I_Two) And (XV), R ′₁, R "₁, Y ', Z_TwoAnd W are as defined above. Has a taste, Z_FourRepresents a formyl group or an esterified carboxy group. ) Of the formula (I)_Two) And (XV)_FourIs a formyl group When represented, these compounds are subjected to an oxidation or reduction reaction to give the following formula (I_Three) Or the following formula (I_Four) (The above formula (I_Three) And (I_Four), R ′₁, R "₁, Z_Two, Y ′ and W are as defined above. Has a taste, Z_FiveIs CH_TwoOH groups or free or at most linear or branched Table 1 shows carboxy groups esterified by alkyl groups containing 6 carbon atoms I forgot. ) Of the formula (XV) or (I_Four)), W substitutes P as described above. When represented, the amine function blocked by P as described above is liberated. After the reaction, the compound of the formula (III) as described above is reacted to give the following formula (I)_Five) (Where R "₁And Y 'have the meaning given above, and R "_TwoAnd R "_ThreeOne of the above is Na Z_FourOr Z_FiveIndependently and SZ as described above_TwoRepresents ) To obtain the compound of ・ Next formula (XVI) (Where R '₁Has the meaning described above, and R ′_TwoAnd R '_ThreeIs R_TwoAnd R_ThreeAbout As defined above, but protected by a protecting group on any of its reactive functional groups. May be. ) Is reacted with a compound of the formula (III) as described above to give a compound of the following formula (I ′) (Where R '₁, R '_Two, R '_ThreeAnd Y 'have the above-mentioned meaning. ) Or a compound of ・ Formula (XVII) (Where R '₁Has the above-mentioned meaning. ) Oxidation reaction of the compound of the following formula (XVIII) (Where R '₁Has the meaning described above, and Z₆And Z₇One or both are free or Represents a steered carboxy group and, if appropriate, Z₆And Z₇The other is C The meaning of the N group is retained. ) And reacting a compound of formula (XVIII) with a compound of formula (III) as described above. And the following equation (I₆) (Where R '₁, Y ', Z₆And Z₇Has the above-mentioned meaning. ) To obtain the compound of   The resulting formula (I₁), (I_Two), (I_Three), (I_Four), (XIV), (XV), (I_Five), (I₆)as well as( I ′) can itself be a compound of formula (I), furthermore a compound of formula (I) or In order to obtain other compounds, the compounds of the above formulas are optionally and optionally added The following conversion reactions: (A) an esterification reaction of an acid functional group, (B) a saponification reaction of the ester function to the acid function, (C) a conversion reaction of an ester function to an acyl function, (D) a conversion reaction of a cyano functional group to an acid functional group, (E) Conversion of the acid function to an amide function and then to an optional thioamide function reaction, (F) a reduction reaction of the carboxy function to the alcohol function, (G) Conversion reaction of alkoxy function to hydroxyl group or hydroxyl function Conversion reaction of to the alkoxy functional group, (H) oxidation reaction of alcohol function to aldehyde, acid or ketone function, (I) a conversion reaction of a formyl group to a carbamoyl group, (J) a conversion reaction of a carbamoyl group to a nitrile group, (K) a conversion reaction of a nitrile group to a tetrazolyl group, (L) conversion of an alkylthio or acylthio group to the corresponding sulfoxide or sulfone Oxidation reaction, (M) the corresponding sulfoximine of sulfide, sulfoxide or sulfone functionality Conversion reaction to (N) a conversion reaction of an oxo functional group to a thioxo functional group, Reaction (where L₁Is as described above. ), (P) The following formula of the acid functional group To a functional group, (Q) Conversion of β-ketosulfoxide function to α-ketothioester function , (R) the conversion of carbamates to ureas, especially the sulfonyl of sulfonyl carbamates Conversion reaction to urea, (S) conversion of the halogenated functionality to a formyl or esterified carboxy functionality Conversion reaction, (T) CH of formyl group_Two-CO_Twoalk or CH = CH-CO_Twoalk (where , Alk represents an alkyl group containing 1 to 4 carbon atoms. ) Followed by a conversion reaction to the corresponding acid, if appropriate (U) Formula of formyl group To a group of the formula Conversion to the group of (V) R '_TwoAnd R '_ThreeOptionally substituted alkyl or as described above for To a group, If it is S-Z_TwoConversion reaction (where alk and Z_TwoHas the above meaning . ), (X) elimination reaction of a protecting group that can be held by the protected reactive functional group, (Y) a salt-forming reaction to obtain the corresponding salts with an inorganic or organic acid or base, (Z) Resolution reaction of racemate to resolved product Characterized by being applied to one or more conversion reactions in any order. The compound of formula (I) thus obtained has all possible racemic, enantiomeric forms And diastereomeric isomers. ) And the formula (I) according to claim 6_D) And a process for producing an addition salt thereof. 12. The formula (I) according to any one of claims 6 to 10_C) And formula (I_D) [Compound (I)_C) And formula (I_D) Are all possible racemic or optical compounds It can be in the active form. ] And formula (I_C) And formula (I_DA) a pharmaceutically acceptable compound Drugs comprising addition salts with inorganic and organic acids or with inorganic and organic bases. 13. A product containing at least one of the agents according to claim 12 as an active ingredient. Drug composition. 14． Formula (IV) as a new industrial compound₁), (IV_Two), (XIII), (XIV) and (XV Wherein Y 'is replaced by a dioxol group and optionally R_TwoAnd R_Threeof A phenyl group optionally substituted by one or more substituents selected from meanings And the optional reactive functional group may be protected by a protecting group. ) Compound. 15. Treatment of diseases resulting from abnormal stimulation of endothelin receptors, especially endothelin receptors. Treatment of hypertension induced by phosphorus, treatment of all vasospasm, cerebral hemorrhage, renal failure Pharmaceutical compositions intended to treat myocardial infarction and prevent recurrence of stenosis after angioplasty Formula (I) according to any one of claims 6 to 10 for the preparation._C) And formula (I_DCompound of) Use of thing.